Treatment of neuropathic pain with 6h-pyrrolo[3,4-d]pyridazine compounds

ABSTRACT

6H-pyrrolo[3,4-d]pyridazine compounds and methods of their use of as ligands of voltage gated calcium channels (VGCC), useful in the treatment of neuropathic pain, and psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, and bipolar disorder, as well as in the treatment of pain, Parkinson&#39;s disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal and other.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed 6H-pyrrolo[3,4-d]pyridazine compounds and method of their use. In particular, this invention is directed to a method of use of 6H-pyrrolo[3,4-d]pyridazine compounds in the treatment of neuropathic pain.

2. Related Background

A major mechanism in many physiological processes, including neurotransmission in the mammalian nervous system, is the opening and closing of voltage gated calcium channels (“VGCC”), also known as voltage sensitive calcium channels (“VSCC”). Such VGCC are formed by the assembly of subunit classes such as alpha 1 and alpha 2. One subunit in the alpha 2 class is the α₂δ subunit. The activity of the calcium channel can be modulated by the activities of the component subunits. For example, gabapentin is known to bind with high affinity to the α₂δ subunit. Four isoforms of this α₂δ protein are known and gabapentin binds with high affinity to 2 of these (α₂δ-1 and α₂δ-2). The relative importance of these two activities in accounting for the efficacy and adverse effects of gabapentin is not known. Compounds that display high-affinity binding to the α₂δ subunit of voltage gated calcium channels have been shown to be efficacious for the treatment of, for example, neuropathic pain. See, J. Biol. Chem., 271(10):5768-5776(1996) and J. Med. Chem., 41:1838-1845(1998). Nonetheless, if one isoform is more controlling of the channel modulation, while the other is less, then compounds that are selective to the controlling isoform are likely to be more efficacious and display fewer side-effects.

Thus, it is desirable to identify other compounds that display high-affinity binding to the α₂δ subunit of voltage gated calcium channels to provide new medicines in the treatment of neuropathic pain. Further, such compounds can be useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases.

International Patent Publication No. WO 01/88101describes a cell line for the expression of an α₂δ2 calcium channel subunit.

6-Methyl-6H-pyrrolo[3,4-d]pyridazine is described in M. M. J. Duflos et al., Tetrahedron Lett., 3453-3454(1973). 1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine, 5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, and 1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine are described in R. Rips et al., J. Org. Chem., 24:551-554(1959). 1,4,5,7-Tetramethyl-6H-pyrrolo[3,4-d]pyridazine, N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzamide, 1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate, and 1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine are described in W. L. Mosby, J. Chem. Soc., 3997-4003(1957). 5,7-Dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine is described in R. Rips et al., J. Org. Chem., 24:372-374(1959).

5,7-Dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide (also known as 5,7-dimethyl-2-(2-oxo-2-phenyl-ethyl)-6H-pyrrolo[3,4-d]pyridazin-2-ium bromide) and 2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafloroborate are described in F. Fuentes-Rodriguez et al., J. Chem. Res. Miniprint, 11:2901-2914(1987). 5,7-Diphenyl-6H-pyrrolo[3,4-d]pyridazine is described in T. Hernandez et al., J. Chem. Soc., Perkins Trans., 1:899-902(1985), and F. F. Rodriguez et al., J. Chem. Res. Miniprint, 11:3001-3001(1987). 5,6,7-Trimethyl-6H-pyrrolo[3,4-d]pyridazine is described in T. Hernandez et al., J. Chem. Soc., Perkin Trans., 1:899-902(1985), F. Fuentes-Rodriguez et al., J. Chem. Res. Miniprint, 11:2901-2914(1987), and R. von Kreher et al., Agnew Chem., 82:958(1970).

1,4-Diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine (also known as 1,4-diphenyl-5,6,7,8-tetrahydro-2,3,8a-triaza-fluorene) and 5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine (also known as 9-methyl-1,4-diphenyl-5,6,7,8-tetrahydro-2,3,8a-triaza-fluorene) are described in T. Uchida et al., J. Heterocycl. Chem., 15:1303-1307(1978). 6-Benzyl-1,4-diphenyl-5-p-tolyl-6H-pyrrolo[3,4-d]pyridazine, 6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine, 6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline (also known as 6,7,10,11-tetraphenyl-5,8,9,11a-tetraaza-benzo[a]fluorene), 11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′.5′:3,4]pyrrolo[1,2-a]quinoxaline (also known as 11-(4-nitro-phenyl)6,7,10-triphenyl-5,8,9,11a-tetraaza-benzo[a]fluorene), and 6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine are described in T. Uchida et al., J. Heterocycl. Chem., 15:241-248(1978).

9,12-Diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline, 5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, and 1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester are described in K. T. Potts et al., J. Org. Chem., 42:1639-1644(1977). 7,10-Diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline, and 11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine (also known as 9,12-diphenyl-10,11,13a-triaza-indeno[1,2-l]phenanthrene) are described in K. T. Potts et al., J. Org. Chem., 44:977-979(1979).

1-Oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2,1-c]benzoxazine-1,4 (also known as 11-hydroxy-5-oxa-8,9,11a-triaza-benzo[a]fluoren-6-one) is described in Kumashiro et al., Nippon Kagaku Zasshi., 82:1072-1074(1961). 10-Methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine, and 11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine are described in M. Noguchi et al., J. Heterocycl. Chem., 22:1049-1053(1985).

1,4-Dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1-chloro-4ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride, 1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, and 1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine are described in S. Inel et al., Tetrahedron, 40:3979-3986(1984).

5-Cyano-1,4-dimethylpyridazino[4,5-a]indolizine (also known as 1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile), 1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and 1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile are described in K. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988). 5-Cyano-1,4-diphenylpyridazino[4,5-a]indolizine (also known as 1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile) is described in K. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988), and K. Matsumoto et al., Heterocycles, 20:1525-1529(1983). 6-Methyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and 1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile are described in K. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988), K. Matsumoto et al., Heterocycles, 34:2239-2242(1992), K. Matsumoto et al., Heterocycles, 20:1525-1529(1983), and K. Matsumoto et al., Can. J. Chem., 71:529-533(1993). 5,7-Dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and 9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile are described in K. Matsumoto et al., Heterocycles, 34:2239-2242(1992), and K. Matsumoto et al., Can. J. Chem., 71:529-533(1993).

Dimethyl 3,12,13,17-tetramethyl-7²,7³-diazabenzo[g]porphyrin-2,18-dipropionate is described in I. A. Chaudhry et al., Aust. J. Chem., 35:1185-11201(1982). 5,6-Dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol, 5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride, and 3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4-d]pyridine (also known as 1-methyl-4,7-diphenyl-3-thia-5,6,8a-triaza-cyclopenta[a]indene) are described in W. Losel et al., Chem. Ber., 118:413-427 (1985). 1,4-Diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole (also known as 1,4-diphenyl-5-thia-2,3,9b-triaza-indeno[2,1-a]indene) is described in N. Abe et al., Bull. Chem. Soc. Japan, 55:200-203(1982).

Nevertheless, there is a need to identify 6H-pyrrolo[3,4-d]pyridazine compounds that display high-affinity binding—particularly selective binding—to the α₂δ subunit of voltage gated calcium channels to provide new medicines in the treatment of neuropathic pain, as well as psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases.

SUMMARY OF THE INVENTION

The present invention is directed to a method of use of 6H-pyrrolo[3,4-d]pyridazine compounds in the treatment of neuropathic pain. The present invention is also directed to the use of 6H-pyrrolo[3,4-d]pyridazine compounds in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases. The present invention is also directed to novel 6H-pyrrolo[3,4-d]pyridazine compounds that selectively bind to α₂δ-1 subunit of Ca channels.

DETAILED DESCRIPTION OF THE INVENTION

A method of treatment of neuropathic pain, and treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, and drug withdrawal of the present invention comprising a step of

administering an effective amount of a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN; NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀-6alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In one aspect, the method of this invention administers an effective amount of a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-aryl optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In an embodiment of this one aspect, the method of this invention administers an effective amount of a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-phenyl optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In another embodiment of this one aspect, the method of this invention administers an effective amount of a compound represented by Formula (I), or a pharmaceutically-acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-phenyl optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl or —C₀₋₆alkyl-phenyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸. —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; and

provided that the compound is not selected from the following table:

In another aspect, this invention is directed to a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R¹ is —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents;

R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; provided that the compound is not

-   6-methyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, -   5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine, -   5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine, -   N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)7benzamide, -   1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate, -   1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine, -   5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, -   5,7-dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide, -   2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazinium     tetrafloroborate -   5,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, -   5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine, -   5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine, -   6-benzyl-1,4-diphenyl-5-p-tolyl-6H-pyrrolo [3,4-d]pyridazine, -   6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine. -   1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine, -   6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline, -   11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′,5′:3,4]pyrrolo[     1,2-a]quinoxaline, -   6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine, -   9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline, -   5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, -   1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid     ethyl ester, -   7,10-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline, -   11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine, -   1-oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2.1-c]benzoxazine-1,4, -   10-methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine, -   11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine, -   1,4-dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, -   1-chloro-4-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, -   1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride, -   1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazinium     tetrafluoroborate, -   1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridazinium     tetrafluoroborate, -   1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium     tetrafluoroborate, -   1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, -   5-cyano-1,4-dimethylpyridazino[4,5-a]indolizine, -   1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine, -   6-methyl-1,4diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   5,7-dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, -   9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile, -   dimethyl     3,12,13,17-tetramethyl-7²,7³-diazabenzo[g]porphyrin-2,18-dipropionate, -   5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol, -   5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride, -   3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4-d]pyridine, or -   1,4-diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole;     and the compound is not selected from the following table:

As used herein, “alkyl” as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like terms include carbon chains containing at least one unsaturated C═C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, “cycloalkenyl” means carbocycles containing no heteroatoms and at least one non-aromatic C═C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

The term “aryl” means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic. The preferred aryl substituents are phenyl and naphthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes a cycloalkyl group connected by a short C₁₋₂alkyl length to the oxy connecting atom.

The term “C₀₋₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group.

The term “hetero” unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a heterocycloC₅alkyl is a five-member ring containing from 4 to no carbon atoms. Examples of heteroaryls include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. Examples of heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroC₀₋₄alkyl” means a heteroalkyl containing 3, 2, 1, or no carbon atoms. However, at least one heteroatom must be present. Thus, as an example, a heteroC₀₋₄alkyl having no carbon atoms but one N atom would be a —NH— if a bridging group and a —NH₂ if a terminal group. Analogous bridging or terminal groups are clear for an O or S heteroatom.

The term “amine” unless specifically stated otherwise includes primary, secondary and tertiary amines substituted with C₀₋₆alkyl.

The term “carbonyl” unless specifically stated otherwise includes a C₀₋₆alkyl substituent group when the carbonyl is terminal.

The term “halogen” includes fluorine, chlorine, bromine and iodine atoms.

The term “optionally substituted” is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the aryl and the alkyl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as “an alkylaryl, the aryl optionally substituted with halogen or hydroxyl.”

Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.

Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes the use of all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without-a definitive stereochemistry at certain positions. The present invention includes the use of all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound used in the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound used in the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions used of 2H-pyrrolo[3,4-c]pyridazine compounds of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs (“NSAID”), ix) GABA-A receptor modulators, x) dopamine agonists or antagonists, xi) selective serotonin reuptake inhibitors (“SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), xii) tricyclic antidepressant drugs, xiv) norepinephrine modulators, xv) L-DOPA, xvi) buspirone, xvii) lithium, xviii) valproate, ixx) neurontin (gabapentin), xx) olanzapine, xxi) nicotinic agonists or antagonists including nicotine, xxii) muscarinic agonists or antagonists, xxiii) heroin substituting drugs such as methadone, levo-alpha-acetylmethadol, buprenorphine and naltrexone, and xxiv) disulfiram and acamprosate. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weight per day are useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian disorders, as well as being useful in the treatment of pain which are responsive to calcium channel modulation, or alternatively about 0.5 mg to about 7 g per patient per day. For example, schizophrenia, anxiety, depression, and panic may be effectively treated by the administration of from about 0.01 mg to 75 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day. Pain may be effectively treated by the administration of from about 0.01 mg to 125 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 5.5 g per patient per day. Further, it is understood that the calcium channel modulating compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

In practice, the compounds used represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions used in the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions used in this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet Or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet, cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient taken one or two tablets, cachets, or capsules, once, twice, or three times daily.

Pharmaceutical compositions used in the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions used in the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions used in the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions used in this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

The compounds and pharmaceutical compositions used in this invention have been found to exhibit biological activity as calcium channel ligands. Accordingly, another aspect of the invention is the treatment in mammals of, for example, schizophrenia, anxiety, depression, panic, bipolar disorders, circadian rhythm and sleep disorders, pain, Parkinson's disease, cognitive dysfunction, epilepsy, drug addiction, drug abuse and drug withdrawal—maladies that are amenable to amelioration through modulation of the calcium channel—by the administration of an effective amount of the compounds of this invention. The term “mammals” includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.

Further, as described above, the compound used in this invention can be utilized in combination with other therapeutic compounds. In particular, the combinations of the calcium channel modulating compound used in this invention can be advantageously used in combination with i) opiate agonists or antagonists, ii) mGluR5 antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs (“NSAID”), ix) GABA-A receptor modulators, x) dopamine agonists or antagonists, xi) selective serotonin reuptake inhibitors (“SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), xii) tricyclic antidepressant drugs, xiii) norepinephrine modulators, xiv) L-DOPA, xv) buspirone, xvi) lithium, xvii) valproate, xviii) neurontin (gabapentin), xix) olanzapine, xx) nicotinic agonists or antagonists including nicotine, xxi) muscarinic agonists or antagonists, xxii) heroin substituting drugs such as methadone, levo-alpha-acetylmethadol, buprenorphine and naltrexone, and xxiii) disulfiram and acamprosate.

The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise. Ac acetyl AIBN 2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol Bn benzyl CAMP cyclic adenosine-3′,5′-monophosphate DAST (diethylamino)sulfur trifluoride DEAD diethyl azodicarboxylate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide Dppf 1,1′-bis(diphenylphosphino)-ferrocene EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃N triethylamine GST glutathione transferase HMDS hexamethyldisilazide LDA lithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPP monoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt 6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylate NBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tol ortho-tolyl OXONE ® 2KHSO₅.KHSO₄.K₂SO₄ PCC pyridinium chlorochromate Pd₂(dba)₃ Bis(dibenzylideneacetone) palladium(0) PDC pyridinium dichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMB para-methoxybenzyl Pye Pyridinediyl r.t. room temperature Rac. Racemic SAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM 2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAF tetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroacetic acid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran Thi Thiophenediyl TLC thin layer chromatography TMS-CN trimethylsilyl cyanide TMSI trimethylsilyl iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS 4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H- xanthene C₃H₅ Allyl

ALKYL GROUP ABBREVIATIONS Me = Methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tetiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl

Assays Demonstrating Biological Activity

The compounds of this invention were tested by the following assays.

Membrane Preparation:

A710 (HEK293 co-expressing α1b, α2δ, β3) cultured in T250 flask were harvested and washed once with buffer A (20 mM HEPES 10 mM EDTA pH=7.4). The pellet was homogenized in buffer A using a Polytron for 20s. After centrifugation for 10 min, the resulting pellet was washed once with the same buffer and twice with buffer B (20 mM HEPES 0.1 mM EDTA pH=7.4). The final pellet was resuspended in the same buffer and aliquoted and stored at −70° C. Protein contents was measured by the Biorad D C method with bovine serum albumin used as standard.

[³H]-GABApentin Binding:

After thawing, the membranes were washed one time with buffer C (50 mM TRIS pH=7.1) and resuspended in ice cold assay buffer (20 mM HEPES pH=7.4), to have a final protein concentration of 50 μg of protein/well. For the competitive binding experiments, the membranes were incubated with 7 nM [³H]-GABApentin for 1 h at rt in the absence or the presence of at least 11 concentrations of the compounds to be tested. The non-specific binding was measured in the presence of 100 μM GABApentin. At the end of the incubation, the suspension was filtered onto 96 well Whatmann GF/B filter plate (Packard) and washed 3 times with ice-cold assay buffer. The plate was dried and 50 μL of microscint 20 (Packard) was added in each well. The plate was sealed and was counted using a Packard Topcount. The plate was counted (2 min) in normal cpm count mode and transforms in DPM with a constant quench correction.

The compounds of this invention displayed efficacy in the above model by IC₅₀ values of less than 10 μM. The compounds the following table, however, gave IC₅₀ values of more than 10 μM:

Spinal Nerve Ligation Model (Chung Model):

The spinal nerve ligation model of neuropathic pain was used to assess the effects of test compounds on nerve injury-induced tactile allodynia (S. H. Kim and J. M. Chung, Pain 50:355-363(1992)). Male Sprague Dawley rats (175-200 g) received unilateral tight ligation of the left L5/L6 spinal nerves distal to the dorsal root ganglion using 4-0 silk suture. Behavioral-nociceptive testing occurred 7-14 days following spinal nerve ligation by placing the rats in chambers on a wire mesh. Rats were tested for tactile allodynia (decreased hindpaw withdrawal threshold to non-noxious punctate stimulation) by applying a series of calibrated von Frey filaments to the plantar aspect of the left hindpaw ipsilateral to the site of nerve injury. The mean 50% hindpaw withdrawal threshold (g.) was determined using the Dixon “up-down” non-parametric test (Chaplan et al., J. Neurosci. Methods, 53:55-63(1994)). Rats that displayed a pre-drug withdrawal threshold >4 g were not considered allodynic and were excluded from the study. Following determination of pre-drug withdrawal thresholds, rats received either an i.p. or p.o. injection of test compound. The effect of the test compound on tactile allodynia was determined over time by measuring hindpaw withdrawal thresholds 30, 60, 90, 120min post-injection. In above model, EXAMPLE 1 produced a 65% effect after i.p. dosing at 30 mg/kg, EXAMPLE 50 produced a 100% effect after i.p. dosing at 20 mg/kg, EXAMPLE 115 produced a 60% effect after i.p. dosing at 30 mg/kg i.p.

The examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied.

Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperature—that is, at a temperature in the range of 18-25° C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60° C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and ‘d’ indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. When given, yields are for illustration only. When given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, “Ar” signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations are used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula I except where defined otherwise.

EXAMPLES 1-47

EXAMPLES 48-84

EXAMPLES 85-370

EXAMPLE 371

EXAMPLE 1 6-(4-ethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of acetonyl acetone (11.7 mL, 100 mmol) and toluene (750 mL) was added p-phenetidine (12.9 mL, 100 mmol) and glacial acetic acid (1 mL). The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.10 (m, 2H), 6.97-6.94 (m, 2H), 5.88 (br s, 2H), 4.08 (q, 2H), 2.02 (s, 6H), 1.46 (t, 3H); MS (ESI) 216 (M+H)⁺.

Acetic anhydride (8.5 mL, 89 mmol) and hydriodic acid (0.48 mL, 6.3 mmol) were added to 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (8.0 g, 37 mmol) under nitrogen and the resulting mixture maintained at 100° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (200 mL), extracted with EtOAc (2×200 mL), and the combined extracts washed with brine (200 mL), dried (MgSO₄), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (15% EtOAc/hexanes) to give 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a tan solid: ¹H NM (CDCl₃, 500 MHz) δ 7.08-7.04 (m, 2H), 6.99-6.96 (m, 2H), 6.30 (s, 1H), 4.08 (q, 2H), 2.41 (s, 3H), 2.29 (s, 3H), 1.97 (s, 3H), 1.45 (t, 3H); MS (ESI) 258 (M+H)⁺.

To a solution of 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and toluene (4 mL) at 0° C. was added dropwise SnCl₄ (0.94 mL, 0.94 mmol, 1.0M solution in CH₂Cl₂) and p-anisoyl chloride (160 mg, 0.94 mmol). The mixture was allowed to warm to rt and heated at 50° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (15 mL), extracted with EtOAc (2×15 mL), and the combined extracts washed with brine (15 mL), dried (MgSO₄), filtered, concentrated in vacuo, and purified by flash chromatography (0-33% EtOAc/hexanes). The resulting residue was dissolved in EtOH (5 mL) and hydrazine (0.5 mL). The solution was stirred at 50° C. overnight, cooled to rt, and concentrated in vacuo to give 6-(4-ethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.57-7.54 (m, 2H), 7.12-7.09 (m, 2H), 7.05-7.03 (m, 2H), 6.99-6.97 (m, 2H), 4.11 (q, 2H), 3.85 (s, 3H), 2.90 (s, 3H), 2.49 (s, 3H), 1.94 (s, 3H), 1.47 (t, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 2 1,4-diethyl-5,7-dimethyl-6-(4-ethoxyphenyl)-6H-pyrrolo[3,4-d]pyridazine

To a solution of 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (EXAMPLE 1) (1.0 g, 4.7 mmol) and toluene (15 mL) at 0° C. was added dropwise SnCl₄ (4.7 mL, 4.7 mmol, 1.0M solution in CH₂Cl₂) and propionyl chloride (0.40 mL, 4.7 mmol). The mixture was warmed to rt and then heated at 50° C. overnight. After cooling to rt, the mixture was quenched with 1N NaOH (50 mL), extracted with EtOAc (2×50 mL), the combined extracts washed with brine (50 mL), dried (MgSO₄), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (0-25% EtOAc/hexanes). The resulting residue was dissolved in EtOH (10 mL) and hydrazine (0.1 mL). The resulting solution was maintained at 50° C. overnight, cooled to rt, and concentrated in vacuo to give 1,4-diethyl-5,7-dimethyl-6-(4-ethoxyphenyl)-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.10 (m, 2H), 7.06-7.03 (m, 2H), 4.12 (q, 2H), 3.11 (q, 4H), 2.40 (s, 6H), 1.48 (t, 3H), 1.39 (t, 6H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 3 6-(4-ethoxyphenyl)-1-ethyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and propionyl chloride (0.08 mL, 0.94 mmol) reacted to give 6-(4-ethoxyphenyl)-1-ethyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.11 (m, 2H), 7.08-7.05 (m, 2H), 4.13 (q, 2H), 3.15 (q, 2H), 2.85 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H), 1.49 (t, 3H), 1.40 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 4 6-(4-ethoxyphenyl)-1-phenyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (EXAMPLE 1) (1.0 g, 4.7 mmol) and toluene (15 mL) at 0° C. was added dropwise SnCl₄ (4.7 mL, 4.7 mmol, 1.0M solution in CH₂Cl₂) and benzoyl chloride (0.54 mL, 4.7 mmol). The mixture was warmed to rt and heated at 50° C. overnight. After cooling to rt, the mixture was diluted with 1N NaOH (50 mL), extracted with EtOAc (2×50 mL), the combined extracts washed with brine (50 mL), dried MgSO₄), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (0-25% EtOAc/hexanes) to give 3-benzoyl-2,5-dimethyl-1-(4ethoxyphenyl)pyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.84-7.82 (m, 2H), 7.52-7.43 (m, 3H), 7.14-7.12 (m, 2H), 7.01-6.98 (m, 2H), 6.18 (s, 1H), 4.10 (q, 2H), 2.33 (s, 3H), 1.98 (s, 3H), 1.47 (t, 3H). MS (ESI) 320 (M+H)⁺.

To a solution of 3-benzoyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (201 mg, 0.63 mmol) and toluene (5 mL) at 0° C. was added dropwise SnCl₄ (0.76 mL, 0.76 mmol, 1.0M solution in CH₂Cl₂) and acetyl chloride (0.06 mL, 0.76 mmol). The mixture was warmed to rt overnight, quenched with 1N NaOH (10 mL), extracted with EtOAc (2×20 mL), the combined extracts washed with brine (50 mL), dried (MgSO₄), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (0-33% EtOAc/hexanes). The resulting residue was dissolved in EtOH (5 mL) and hydrazine (0.1 mL). The solution was stirred at rt overnight and concentrated in vacuo to give 6-(4-ethoxyphenyl)-1-phenyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.62-7.59 (m, 2H), 7.47-7.44 (m, 3H), 7.12-7.09 (m, 2H), 7.05-7.02 (m, 2H), 4.11 (q, 2H), 2.89 (s, 3H), 2.49 (s, 3H), 1.87 (s, 3H), 1.47 (t, 3H). MS (ESI) 358 (M+H)⁺.

EXAMPLE 5 6-(4-ethoxyphenyl)-1-(3-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and m-anisoyl chloride (0.13 mL, 0.94 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(3-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.33 (m, 1H), 7.18-7.14 (m, 2H), 7.13-7.08 (m, 2H), 7.07-7.02 (m, 2H), 7.01-6.97 (m, 1H), 4.11 (q, 2H), 3.84 (s, 3H), 2.96 (s, 3H), 2.51 (s, 3H), 1.92 (s, 3H), 1.47 (t, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 6 6-(4-ethoxyphenyl)-1-(3-benzyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and phenacetyl chloride (0.16 mL, 0.94 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(3-benzyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.38-7.33 (m, 1H), 7.18-7.14 (m, 3H), 7.13-7.08 (m, 2H), 7.07-7.02 (m, 2H), 7.01-6.97 (m, 1H), 4.51 (s, 2H), 4.11 (q, 2H), 3.84 (s, 3H), 2.96 (s, 3H), 2.51 (s, 3H), 1.92 (s, 3H), 1.47 (t, 3H); MS (ESI) 372 (M+H)⁺.

EXAMPLE 7 1-(4chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and 4-chlorobenzoyl chloride (0.14 mL, 0.94 mmol) reacted to give 1-(4-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.58-7.53 (m, 2H), 7.46-7.41 (m, 2H), 7.14-7.08 (m, 2H), 7.07-7.02 (m, 2H), 4.11 (q, 2H), 2.94 (s, 3H), 2.51 (s, 3H), 1.91 (s, 3H), 1.48 (t, 3H); MS (ESI) 392 (M+H)⁺.

EXAMPLE 8 6-(4-ethoxyphenyl)-1-(2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and o-anisoyl chloride (0.14 mL, 0.94 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(2-methoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H N (CDCl₃, 500 MHz) δ 7.47-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.17-7.12 (m, 1H), 7.10-7.01 (m, 4H), 7.00-6.95 (m, 1H), 4.10 (q, 2H), 3.73 (s, 3H), 2.96 (s, 3H), 2.49 (s, 3H), 1.77 (s, 3H), 1.47 (t, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 9 1-(3chlorophenyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and 3-chlorobenzoyl chloride (0.12 mL, 0.94 mmol) reacted to give 1-(3-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.62-7.58 (m, 1H), 7.53-7.48 (m, 1H), 7.44-7.37 (m, 2H), 7.14-7.09 (m, 2H), 7.07-7.03 (m, 2H), 4.11 (q, 2H), 2.97 (s, 3H), 2.51 (s, 3H), 1.91 (s, 3H), 1.47 (t, 3H); MS (ESI) 392 (M+H)⁺.

EXAMPLE 10 1-(2-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (200 mg, 0.78 mmol) and 2-chlorobenzoyl chloride (0.12 mL, 0.94 mmol) reacted to give 1-(2-chlorophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.48-7.43 (m, 2H), 7.40-7.34 (m, 2H), 7.17-7.12 (m, 1H), 7.08-6.99 (m, 3H), 4.10 (q, 2H), 2.93 (s, 3H), 2.50 (s, 3H), 1.74 (s, 3H), 1.46 (t, 3H); MS (ESI) 392 (M+H)⁺.

EXAMPLE 11 6-(4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and p-toluoyl chloride (0.13 mL, 1.0 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.50 (d, 2H), 7.26 (d, 2H), 7.12-7.10 (m, 2H), 7.05-7.03 (m, 2H), 4.11 (q, 2H), 2.93 (s, 3H), 2.50 (s, 3H), 2.41 (s, 3H), 1.91 (s, 3H), 1.47 (t, 3H); MS ESI) 372 (M+H)⁺.

EXAMPLE 12 6-(4-ethoxyphenyl)-1-(4-ethylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and 4-ethylbenzoyl chloride (0.15 mL, 1.0 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(4-ethylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.54-7.51 (m, 2H), 7.29-7.25 (m, 2H), 7.12-7.09 (m, 2H), 7.06-7.03 (m, 2H), 4.11 (q, 2H), 2.93 (s, 3H), 2.71 (q, 2H), 2.50 (s, 3H), 1.91 (s, 3H), 1.47 (t, 3H), 1.26 (t, 3H); MS (ESI) 386 (M+H)⁺.

EXAMPLE 13 1-(1-cyclopentethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and 3-cyclopentylpropionyl chloride (0.18 mL, 1.2 mmol) reacted to give 1-(1-cyclopentylethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.09 (m, 2H), 7.07-7.03 (m, 2H), 4.11 (q, 2H), 3.09 (dd, 2H), 2.77 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 1.98-1.89 (m, 1H), 1.87-1.77 (m, 4H), 1.63-1.56 (m, 2H), 1.55-1.47 (m, 2H), 1.48 (t, 3H), 1.20-1.15 (m, 2H); MS (ESI) 378 (M+H)⁺.

EXAMPLE 14 1-(4-ethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and 4-ethoxybenzoyl chloride (185 mg, 1.0 mmol) reacted to give 1-(4-ethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.55 (d, 2H), 7.12-7.09 (m, 2H), 7.05-7.03 (m, 2H), 6.97 (d, 2H), 4.14-4.06 (m, 4H), 2.93 (s, 3H), 2.50 (s, 3H), 1.94 (s, 3H), 1.47 (t, 3H), 1.43 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 15 1-(cyclopropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and cyclopropanecarbonyl chloride (0.11 mL, 1.2 mmol) reacted to give 1-(cyclopropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.14-7.10 (m, 2H), 7.07-7.03 (m, 2H), 4.12 (q, 2H), 2.76 (s, 3H), 2.52 (s, 3H), 2.42 (s, 3H), 2.38 (quintet, 1H), 1.49 (t, 3H), 1.34-1.32 (m, 2H), 0.99-0.96 (m, 2H); MS (ESI) 322 (M+H)⁺.

EXAMPLE 16 6-(4-ethoxyphenyl)-1-(2-methylpropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and isovaleryl chloride (0.15 mL, 1.2 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(2-methylpropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.09 (m, 2H), 7.06-7.03 (m, 2H), 4.12 (q, 2H), 2.94 (d, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H), 2.18-2.10 (m, 1H), 1.48 (t, 3H), 1.01 (d, 6H); MS (ESI) 338 (M+H)⁺.

EXAMPLE 17 1-(cyclopentyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and cyclopentanecarbonyl chloride (0.15 mL, 1.2 mmol) reacted to give 1-(cyclopentyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.09 (m, 2H), 7.06-7.02 (m, 2H), 4.12 (q, 2H), 3.67 (quintet, 1H), 2.77 (s, 3H), 2.42 (s, 6H), 2.26-2.19 (m, 2H), 2.02-1.93 (m, 2), 1.92-1.84 (m, 2H) 1.70-1.63 (m, 2H), 1.48 (t, 3H); MS (ESI) 350 (M+H)⁺.

EXAMPLE 18 1-(cyclopentylmethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and cyclopentylacetyl chloride (176 mg, 1.2 mmol) reacted to give 1-(cyclopentylmethyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.09 (m, 2H), 7.06-7.02 (m, 2H), 4.12 (q, 2H), 3.08 (d, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.41-2.32 (m, 1H), 1.79-1.72 (m, 2H), 1.70-1.62 (m, 2H) 1.55-1.46 (m, 2H), 1.48 (t, 3H), 1.44-1.37 (m, 2H); MS (ESI) 364 (M+H)⁺.

EXAMPLE 19 1-(cyclohexyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and cyclohexanecarbonyl chloride (0.16 mL, 1.2 mmol) reacted to give 1-(cyclohexyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.08 (m, 2H), 7.06-7.02 (m, 2H), 4.12 (q, 2H), 3.14 (tt, 1H), 2.77 (s, 3), 2.41 (s, 3H), 2.39 (s, 31), 2.04-1.98 (m, 2H-), 1.95-1.82 (m, 4H), 1.78-1.72 (m, 1H) 1.48 (t, 3H), 1.44-1.34 (m, 3H); MS (ESI) 364 (M+H)⁺.

EXAMPLE 20 6-(4-ethoxyphenyl)-1-pentyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol)-and hexanoyl chloride (0.17 mL, 1.2 mmol) reacted to give 6-(4-ethoxyphenyl)-1-penyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13-7.09 (m, 2H), 7.06-7.03 (m, 2H), 4.12 (q, 2H), 3.06 (dd, 2H), 2.77 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H), 1.81-1.75 (m, 2H), 1.50-1.44 (m, 2), 1.48 (t, 3H), 1.42-1.34 (m, 2H), 0.89 (t, 3H); MS (ESI) 352 (M+H)⁺.

EXAMPLE 21 6-(4-ethoxyphenyl)-1-(4-fluorophenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and 4-fluorobenzoyl chloride (0.12 mL, 1.0 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(4-fluorophenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellowish solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.62-7.58 (m, 2H), 7.18-7.08 (m, 4H), 7.07-7.03 (m, 2H), 4.11 (q, 2H), 2.95 (s, 3H), 2.51 (s, 3H), 1.91 (s, 3H), 1.48 (t, 3H); MS (ESI) 376 (M+H)⁺.

EXAMPLE 22 6-(4-ethoxyphenyl)-1-(2,2,4-trimethylpentyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and 3,5,5-trimethylhexanoyl chloride (0.23 mL, 1.2 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(2,2,4-trimethylpentyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid:

¹H NMR (CDCl₃, 500 MHz) δ 7.14-7.08 (m, 2H), 7.06-7.03 (m, 2H), 4.12 (q, 2H), 2.99 (dd, 1H), 2.92 (dd, 1H), 2.78 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.15 (quintet, 1H), 1.53 (dd, 1H), 1.49 (t, 3H), 1.21 (dd, 1H), 1.02 (d, 3H), 0.82 (s, 9H); MS (ESI) 394 (M+H)⁺.

EXAMPLE 23 6-(4-ethoxyphenyl)-1-(1-phenylethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and hydrocinnamoyl chloride (0.18 mL, 1.2 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(1-phenylethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 7.12-7.09 (m, 2H), 7.06-7.04 (m, 2H), 4.12 (q, 2H), 3.38 (dd, 2H), 3.15 (dd, 2H), 2.79 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.48 (t, 3H); MS (ESI) 386 (M+H)⁺.

EXAMPLE 24 1-(2,2-dimethylpropyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and tert-butylacetyl chloride (0.17 mL, 1.2 mmol) reacted to give 1-(2,2-dimethylpropyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12-7.08 (m, 2H), 7.06-7.02 (m, 2H), 4.12 (q, 2H), 3.03 (s, 2H), 2.79 (s, 3H), 2.43 (s, 3H), 2.42 (s, 3H), 1.48 (t, 3H), 1.06 (s, 9H); MS (ESI) 352 (M+H)⁺.

EXAMPLE 25 6-(4-ethoxyphenyl)-1-(4-methoxyphenylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and 4-methoxyphenylacetyl chloride (0.19 mL, 1.2 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(4-methoxyphenylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.16 (d, 2H), 7.05-6.98 (m, 4H), 6.76 (d, 2H), 4.39 (s, 2H), 4.09 (q, 2H), 3.74 (s, 3H), 2.81 (s, 3H), 2.41 (s, 3H), 2.19 (s, 3H), 1.46 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 26 6-(4-ethoxyphenyl)-1-(4-(trifluoromethoxy)phenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.16 mL, 1.0 mmol) reacted to give the product which was taken up in hot ether, precipitated with HCl in ether, and filtered to give 6-(4-ethoxyphenyl)-1-(4-(trifluoromethoxy)phenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow solid: ¹H NMR (d₆-DMSO, 500 MHz) δ 7.86 (d, 2H), 7.62 (d, 2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.14 (q, 2H), 3.14 (s, 3H), 2.60 (s, 3H), 1.94 (s, 3H), 1.38 (t, 3H); MS (ESI) 442 (M+H)⁺.

EXAMPLE 27 6-(4-ethoxyphenyl)-1-(3-methoxyphenylmethyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyrdazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (257 mg, 1.0 mmol) and 3-methoxyphenylacetyl chloride (0.19 mL, 1.2 mmol) reacted to give 6-(4-ethoxyphenyl)-1-(3-methoxyphenylmethyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.15 (dd, 1H), 7.06-7.03 (m, 2H), 7.02-6.98 (m, 2H), 6.83 (d, 1H), 6.80 (s, 1H), 6.71 (d, 1H), 4.43 (s, 2H), 4.09 (q, 2H), 3.72 (s, 3H), 2.81 (s, 3H), 2.42 (s, 3H), 2.20 (s, 3H), 1.46 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 28 1-(4-bromophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and p-bromobenzoyl chloride (220 mg, 1.0 mmol) reacted to give the product which was taken up in hot ether, precipitated with HCl in ether, and filtered to give 1-(4-bromophenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.83 (d, 2H), 7.66 (d, 2H), 7.37 (d, 2H), 7.20 (d, 2H), 4.14 (q, 2H), 3.12 (s, 3H), 2.59 (s, 3H), 1.94 (s, 3H), 1.38 (t, 3H); MS (ESI) 437 (M+H)⁺.

EXAMPLE 29 1-(2,4-dimethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and 2,4-dimethoxybenzoyl chloride (201 mg, 1.0 mmol) reacted to give the product which was taken up in hot ether, precipitated with HCl in ether, and filtered to give 1-(2,4-dimethoxyphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.41-7.30 (m, 3H), 7.18 (d, 2H), 6.80-6.73 (m, 2H), 4.14 (q, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.03 (br s, 3H), 2.54 (s, 3H), 1.87 (s, 3H), 1.38 (t, 3H); MS (ESI) 418 (M+H)⁺.

EXAMPLE 30 1-(4-biphenyl)-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (214 mg, 0.83 mmol) and 4-biphenylcarbonyl chloride (217 mg, 1.0 mmol) reacted to give 1-(4-biphenyl)-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.73-7.64 (m, 4H), 7.60 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.11 (d, 2H), 7.03 (d, 2H), 4.11 (q, 2H), 2.87 (s, 3H), 2.49 (s, 3H), 1.95 (s, 3H), 1.47 (t, 3H); MS (ESI) 434 (M+H)⁺.

EXAMPLE 31 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid methyl ester

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) and methyl 5-chloro-5-oxovalerate (0.63 mL, 4.5 mmol) reacted to give 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.05 (d, 2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.65 (s, 3H), 2.75 (t, 2H), 2.41 (s, 3H), 2.40 (t, 2H), 2.11 (s, 3H), 2.01 (s, 3H), 2.00 (quintet, 2H), 1.45 (t, 3H); MS (ESI) 386 (M+H)⁺.

To a solution of 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester (250 mg, 0.65 mmol) in ethanol (1 mL) was added a 1.0M solution of hydrazine in ethanol (0.72 mL, 0.72 mmol). The solution was stirred overnight at rt and concentrated in vacuo to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.11-7.08 (m, 2H), 7.05-7.03 (in, 2H), 4.11 (q, 2H), 3.63 (s, 3H), 3.12 (t, 2H), 2.77 (s, 3H), 2.51 (t, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.14 (quintet, 2H), 1.47 (t, 3H); MS (ESI) 382 (M+H)⁺.

EXAMPLE 32 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]propionic acid methyl ester

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) and methyl 4-chloro-4-oxobutyrate (0.56 mL, 4.5 mmol) reacted to give 4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]4-oxo-butyric acid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.67 (s, 3H), 3.03 (t, 211), 2.74 (t, 2H), 2.41 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.45 (t, 3H); MS (ESI) 372 (M+H)⁺.

To a solution of 4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-4-oxo-butyric acid methyl ester (250 mg, 0.67 mmol) in ethanol (1 mL) was added a 1.0M solution of hydrazine in ethanol (0.74 mL, 0.74 mmol). The solution was stirred overnight at rt and concentrated in vacuo to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionic acid methyl ester as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.11-7.08 (m, 2H), 7.06-7.03 (m, 2H), 4.12 (q, 2H), 3.70 (s, 3), 3.43 (t, 2H), 3.00 (t, 2H), 2.79 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H), 1.48 (t, 3H); MS (ESI) 368 (M+H)⁺.

EXAMPLE 33 1-(cyclopropyl)-6-(2,4-dimethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone (5.88 mL, 50 mmol) and 2,4-dimethoxyaniline (7.12 mL, 50 mmol) reacted to give 1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.08 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 5.90 (s, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 1.97 (s, 6H); MS (ESI) 232 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1, 1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (2.31 g, 10 mmol), acetic anhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reacted to give 3-acetyl-1-(2,4dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.02 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 6.32 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H); MS (ESI) 274 (M+H)⁺.

To a solution of 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (273 mg, 1.0 mmol) in toluene (5 mL) at −78° C. was added 3-cyclopropanecarbonyl chloride (0.11 mL, 1.2 mmol) followed by dropwise addition of a 1.0M solution of tin(IV) chloride in CH₂Cl₂ (1.2 mL, 1.2 mmol). The reaction was allowed to warm to room temp overnight. The solution was diluted with 0.25M NaOH, extracted with EtOAc, the organic layer washed with brine, dried over MgSO₄, filtered, concentrated in vacuo, and purified by flash chromatography (10-25% EtOAc/hexanes) to give the dione (MS (ESI) 342 (M +H)⁺). The dione was taken up in ethanol (5 mL) and excess hydrazine (0.1 mL) was added. The solution was stirred at 40° C. overnight, poured into water, and filtered to give 1-(cyclopropyl)-6-(2,4-dimethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.03 (dd, 1H), 6.66-6.56 (m, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 2.75 (s, 3H), 2.47 (s, 3H), 2.39 (quintet, 1H), 2.38 (s, 3H), 1.35-1.28 (m, 2H), 0.97 (dd, 2H); MS (ESI) 338 (M+H)⁺.

EXAMPLE 34 6-(2,4-dimethoxyphenyl)-1-(4-methylphenl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 33, 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (273 mg, 1.0 mmol) and p-toluoyl chloride (0.27 mL, 2.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(2,4-dimethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.58-7.51 (m, 2H), 7.45-7.37 (m, 2H), 7.33 (dd, 1H), 6.92 (d, 1H), 6.79 (dd, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.08 (br s, 3H), 2.50 (br s, 3H), 2.44 (s, 3H), 1.90 (s, 3H); MS (ESI) 388 (M+H)⁺.

EXAMPLE 35 6-(2,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 33, 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (273 mg, 1.0 mmol) and p-anisoyl chloride (0.28 mL, 2.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(2,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.58-7.51 (m, 2H), 7.45-7.37 (m, 2H), 7.33 (dd, 1H), 6.92 (d, 1H), 6.79 (dd, 1H), 3.90 (s, 3H), 3.87 (s 3H), 3.77 (s, 3H), 3.08 (br s, 3H), 2.50 (s, 3H), 2.00 (s, 3H); MS (ESI) 404 (M+H)⁺.

EXAMPLE 36 1-(cyclopropyl)-6-(4-ethoxy-2-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone (5.88 mL, 50 mmol) and o-cresol (6.12, 50 mmol) reacted to give 1-(4-hydroxy-2-methylphenyl)-2,5-dimethylpyrrole as a colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ 7.05 (d, 1H), 6.80 (d, 1H), 6.75 (dd, 1H), 5.96 (s, 2H), 5.10 (br s, 1H), 1.96 (s, 6H), 1.92 (s, 3H); MS (ESI) 202 (M+H)⁺.

To a solution of 1-(4-hydroxy-2-methylphenyl)-2,5-dimethylpyrrole (˜50 mmol) in acetonitrile (300 mL) was added potassium carbonate (55 mmol) and an excess of bromoethane (>100 mmol). The reaction mixture was stirred at 50° C. overnight, cooled to room temperature, and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO₄, filtered, concentrated in vacuo, and purified by column chromatography (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ 7.07 (d, 1H), 6.84 (d, 1H), 6.79 (dd, 1H), 5.90 (s, 2H), 4.07 (q, 2H), 1.92 (s, 6H), 1.90 (s, 3H), 1.45 (t, 3H; MS (ESI) 230 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1, 2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (2.29 g, 10 mmol), acetic anhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reacted to give 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.99 (d, 1H), 6.85 (d, 1H), 6.79 (dd, 1H), 6.32 (s, 1H), 4.06 (q, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.44 (t, 3H); MS (ESI) 272 (M +H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (271 mg, 1.0 mmol) and 3-cyclopropanecarbonyl chloride (0.11 mL, 1.2 mmol) reacted to give 1-(cyclopropyl)-6-(4-ethoxy-2-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.03 (d, 1H), 6.92 (d, 1H), 6.88 (dd, 2H), 4.10 (q, 2H), 2.76 (s, 3H), 2.45 (s, 3H), 2.38 (quintet, 1H), 2.35 (s, 3H), 1.83 (s, 3H), 1.47 (t, 3H), 1.39-1.31 (m, 2H), 0.98 (dd, 2H); MS (ESI) 336 (M+H)⁺.

EXAMPLE 37 6-(4-ethoxy-2-methylphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 36, 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (271 mg, 1.0 mmol) and p-toluoyl chloride (0.27 mL, 2.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(4-ethoxy-2-methylphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.63-7.59 (m, 2H), 7.47-7.39 (m, 2H), 7.24 (d, 1H), 7.13 (d, 1H), 7.03 (dd, 1H), 4.12 (q, 2H), 3.09 (br s, 3H), 2.51 (br s, 3H), 2.44 (s, 3H), 1.89 (s, 3H), 1.83 (s, 3H), 1.37 (t, 3H); MS (ESI) 386 (M+H)⁺.

EXAMPLE 38 6-(4-ethoxy-2-methylphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 36, 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methylphenyl)pyrrole (271 mg, 1.0 mmol) and p-anisoyl chloride (0.28 mL, 2.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(4-ethoxy-2-methylphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.63-7.59 (m, 2H), 7.47-7.39 (m, 2H), 7.24 (d, 1H), 7.13 (d, 1H), 7.03 (dd, 1H), 4.12 (q, 2H), 3.87 (s, 3H), 3.09 (br s, 3H), 2.51 (br s, 3H), 2.44 (s, 3H), 1.89 (s, 3H), 1.37 (t, 3H); MS (ESI) 404 (M+H)⁺.

EXAMPLE 39 6-(3-chloro-4-ethoxyphenyl)-1-(cyclopropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone (0.83 mL, 7.0 mmol) and 4-amino-2-chlorophenol (1.0 g, 7.0 mmol) reacted to give 1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole as a brown solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.22 (d, 1H), 7.10 (d, 1H), 7.05 (dd, 1H), 5.88 (s, 2H), 5.66 (br s, 1H), 2.03 (s, 6H); MS (ESI) 222 (M+H)⁺.

Using the general procedure outlined in EXAMPLE 1, 1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole (1.11 g, 5 mmol) and an excess of bromoethane (1.0 mL) reacted to give 1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.27 (d, 1H), 7.08 (dd, 1H), 6.99 (dd, 1H), 5.89 (s, 2H), 4.18 (q, 2H), 2.04 (s, 6H), 1.53 (t, 3H); MS (ESI) 250 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1, 1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (1.21 g, 4.8 mmol), acetic anhydride (5 mL), and hydriodic acid (0.07 mL, 0.83 mmol) reacted to give 3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.21 (d, 1H), 7.04-6.98 (m, 2H), 6.29 (s, 1H), 4.17 (q, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 1.98 (s, 3H), 1.52 (t, 3H); MS (ESI) 292 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (291 mg, 1.0 mmol) and 3-cyclopropanecarbonyl chloride (0.18 mL, 2.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(3-chloro-4-ethoxyphenyl)-1-(cyclopropyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.70 (s, 1H), 7.46-7.41 (m, 2H), 4.26 (q, 2), 2.99 (br s, 3H), 2.67-2.61 (m, 1H), 2.58 (s, 3H), 2.52 (s, 3H), 1.43 (t, 3H), 1.28-1.12 (m, 4H); MS (ESI) 356 (M+H)⁺.

EXAMPLE 40 6-(3-chloro-4-ethoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 39, 3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (291 mg, 1.0 mmol) and p-toluoyl chloride (0.27 mL, 2.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(3-chloro-4-ethoxyphenyl)-1-(4- methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a green solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.71 (d, 1H), 7.63-7.57 (m, 2H), 7.45-7.39 (m, 4H), 4.25 (q, 2H), 3.08 (br s, 3H), 2.44 (s, 3H), 1.96 (s, 3H), 1.41 (t, 3H); MS (ESI) 406 (M+H)⁺.

EXAMPLE 41 1-(cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

To a solution of 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (2.73 g, 10 mmol) (EXAMPLE 33) in CH₂Cl₂at rt (75 mL) was added a 1.0M solution of boron tribromide in CH₂Cl₂ (15 mL, 15 mmol) and the reaction monitored by LC. After complete consumption of the starting material, the reaction was carefully quenched with saturated NaHCO₃ and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO₄, filtered, concentrated in vacuo, and purified by flash chromatography to give 3-acetyl-2,5-dimethyl-1-(4-hydroxy-2-methoxyphenyl)pyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.92 (d, 1H), 6.61 (d, 1H), 6.54 (dd, 1H), 6.32 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.93 (s, 3H), 1.69 (br s, 1H); MS (ESI) 260 (M+H)⁺.

Using the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-hydroxy-2-methoxyphenyl)pyrrole (1.37 g, 5.3 mmol) and an excess of bromoethane (2.0 mL) reacted to give 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.99 (d, 1H), 6.59 (d, 1H), 6.53 (dd, 1H), 6.31 (s, 1H), 4.08 (q, 2H), 3.74 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H), 1.46 (t, 3H); MS (ESI) 288 (M+H)⁺.

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole (241 mg, 0.84 mmol) and 3-cyclopropanecarbonyl chloride (0.10 mL, 1.0 mmol) reacted to give the product which was taken up in ether, precipitated with HCl in ether, and filtered to give 1-(cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.29 (d, 1H), 6.92 (d, 1H), 6.79 (dd, 2H), 4.18 (q, 2H), 3.77 (s, 3H), 3.45 (br s, 3H), 2.99 (br s, 3H), 2.64 (m, 1H), 2.46 (s, 3H), 1.40 (t, 3H), 1.20-1.12 (m, 4H); MS (ESI) 352 (M+H)⁺.

EXAMPLE 42 6-(4-ethoxy-2-methoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole (EXAMPLE 34) (241 mg, 0.84 mmol) and p-toluoyl chloride (0.13 mL, 1.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(4-ethoxy-2-methoxyphenyl)-1-(4-methylphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.59-7.53 (m, 2H), 7.46-7.42 (m, 2H), 7.28 (d, 1H), 6.88 (d, 1H), 6.76 (dd, 1H), 4.15 (q, 2H), 3.75 (s, 3H), 3.56 (br s, 3H), 3.10 (br s, 3H), 2.43 (s, 3H), 1.89 (s, 3H), 1.38 (t, 3H); MS (ESI) 402 (M+H)⁺.

EXAMPLE 43 6-(4-ethoxy-2-methoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride

Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxy-2-methoxyphenyl)pyrrole (EXAMPLE 35) (241 mg, 0.84 mmol) and p-anisoyl chloride (0.15 mL, 1.0 mmol) reacted to give the product as a clear oil which was taken up in ether, precipitated with HCl in ether, and filtered to give 6-(4-ethoxy-2-methoxyphenyl)-1-(4-methoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a yellow solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.69-7.62 (m, 2H), 7.29 (d, 1H), 7.19-7.13 (m, 2H), 6.90 (d, 1H), 6.77 (dd, 1H), 4.16 (q, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.65 (br s, 3H), 3.05 (br s, 3H), 1.93 (s, 3H), 1.38 (t, 3H); MS (ESI) 418 (M+H)⁺.

EXAMPLE 44 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid hydrazide

To a solution of 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester (100 mg, 0.26 mmol) (EXAMPLE 31) in ethanol (1 mL) was added excess hydrazine (0.1 mL). The solution was stirred overnight at 50° C. and concentrated in vacuo to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid hydrazide as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 9.04 (br s, 1H), 7.12-7.09 (m, 2H), 7.06-7.03 (m, 2H), 4.11 (q, 2H), 3.78 (br s, 2H), 3.15 (t, 2H), 2.78 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 2.32 (t, 2H), 2.18-2.12 (m, 2H), 1.48 (t, 3H); MS (ESI) 382 (M+H)⁺.

EXAMPLE 45 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid potassium salt

To a solution of 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid methyl ester (104 mg, 0.27 mmol) (EXAMPLE 31) in THF (3 mL) was added potassium trimethylsilanoate (57 mg, 0.4 mmol). The mixture was stirred overnight and filtered to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid potassium salt as a tan solid: ¹NMR (DMSO-d₆, 500 MHz) δ 7.27 (d, 2H), 7.12 (d, 2H), 4.12 (q, 2H), 2.90 (t, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H), 1.91 (t, 2H), 1.80-1.75 (m, 2H), 1.37 (t, 3H); MS (ESI) 368 (M+H)⁺.

EXAMPLE 46 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionic acid hydrazide

Utilizing the general procedure outlined in EXAMPLE 44, 4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-4oxo-butyric acid methyl ester (100 mg, 0.27 mmol) (EXAMPLE 32) and excess hydrazine (0.1 mL) reacted to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionic acid hydrazide as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.62 (br s, 1H), 7.13-7.08 (m, 2H), 7.07-7.04 (m, 2H), 4.12 (q, 2H), 3.49 (t, 2H), 3.09 (br s, 2H), 2.91 (t, 2H), 2.83 (s, 3H), 2.46 (s, 3H), 2.44 (s, 3), 1.49 (t, 3H); MS (ESI) 368 (M+H)⁺.

EXAMPLE 47 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionic acid potassium salt

Utilizing the general procedure outlined in EXAMPLE 45, 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionic acid methyl ester (100 mg, 0.27 mmol) (EXAMPLE 32) and potassium trimethylsilanoate (57 mg, 0.4 mmol) reacted to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-propionic acid potassium salt as a tan solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.27 (d, 2H), 7.12 (d, 2H), 4.12 (q, 2H), 3.09 (dd, 2H), 2.63 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H), 2.15 (dd, 2H), 1.37 (t, 3H); MS (ESI) 354 (M+H)⁺.

EXAMPLE 48 1,4,5,7-tetramethyl-6-[4-(trifluoromethoxy)phenyl]-6H-pyrrolo[3,4-d]pyridazine

A solution of 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-trifluoromethoxy aniline (170 μL, 1.26 mmol) was refluxed in EtOH (5 mL)/AcOH (1%) for 48 h. Hydrazine (100 μL, 3.15 mmol) was added and the mixture was refluxed for 1 h. The reaction mixture was poured into ice water (50 mL). The resulting precipitate was filtered and dried under vacuum to afford 1,4,5,7-tetramethyl-6-[4-(trifluoromethoxy)phenyl]-6H-pyrrolo[3,4-d]pyridazine as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.42 (d, 2H), 7.25 (d, 2H), 2.81 (s, 6H), 2.41 (s, 6H); MS (ESI) 336 (M+H)⁺.

EXAMPLE 49 6-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48, 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-isopropyl aniline (172 μL, 1.26 mmol) reacted to give 6-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.40 (d, 2H), 7.07 (d, 2H), 3.01-2.97 (m, 1H) 2.83 (s, 6H), 2.41 (s, 6H) 1.28 (d, 6H); MS (ESI) 294 (M+H)⁺.

EXAMPLE 50 6-(4-ethoxy)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48, 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and p-phenetidine (172 μL, 1.26 mmol) reacted to give 6-(4-ethoxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d, 2H), 4.07 (q, 2H), 2.83 (s, 6H), 2.41 (s, 6H) 1.45 (t, 6H); MS (ESI) 294 (M+H)⁺.

EXAMPLE 51 6-(2-ethoxy)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48, 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and o-phenetidine (172 μL, 1.26 mmol) reacted to give 6-(2-ethoxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d, 2H), 4.12 (q, 2H), 2.83 (s, 6H), 2.41 (s, 6H) 1.55 (t, 6H); MS (ESI) 294 (M+H)⁺.

EXAMPLE 52 6-(4-hydroxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 48, 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-aminophenol (172 μL, 1.26 mmol) reacted to give 6-(4-hydroxyphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a tan solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d, 2H), 2.83 (s, 6H), 2.41 (s, 6H); MS (ESI) 266 (M+H)⁺.

EXAMPLE 53 6-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-isopropyl aniline (172 μL, 1.26 mmol) reacted to give 6-(4-isopropylphenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a tan solid. ¹H NM (CDCl₃, 500 MHz) δ 7.41-7.39 (d, 2H), 7.07-7.06 (d, 2H), 3.01-2.97 (m, 1H) 2.83 (s, 6H), 2.41 (s, 6H) 1.28-1.27 (d, 6H). MS 294 (M+H).

EXAMPLE 54 6-(6-Ethoxy-pyridin-3-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 6-ethoxy-pyridin-3-yl amine (140 mg, 1.0 mmol) reacted to give 6-(6-Ethoxy-pyridin-3-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.04 (s, 1H), 7.41 (d, 1H), 6.93 (d, 1H), 4.46 (q, 1H), 2.80 (s, 6H), 2.45 (s, 6H), 1.46 (t, 3H); MS (ESI) 297 (M+H)⁺.

EXAMPLE 55 6-(5-Ethoxy-pyrazin-2-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane

(200 mg, 1.0 mol) and 5-ethoxy-pyrazin-2-yl amine (130 mg, 1.0 mmol) reacted to give 6-(5-ethoxy-pyrazin-2-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.27 (s, 1H), 8.11 (s, 1H), 4.50 (q, 1H), 2.80 (s, 6H), 2.48 (s, 6H), 1.50 (t, 3H); MS (ESI) 298 (M+H)⁺.

EXAMPLE 56 1,4,5,7-Tetramethyl-6-(5-propoxy-pyridin-2-yl)-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (100 mg, 0.5 mol) and 5-ethoxy-pyrazin-2-yl amine (80 mg, 0.5 mmol) reacted to give 1,4,5,7-tetramethyl-6-(5-propoxy-pyridin-2-yl)-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.35 (s, 1H), 7.44 (d, 1H), 7.22 (d, 1H), 4.08 (t, 2H), 2.80 (s, 6H), 2.45 (s, 6H), 1.89 (q, 2H), 1.10 (t, 3H); MS (ESI) 311 (M+H)⁺.

EXAMPLE 57 2-Chloro-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol

Utilizing the general procedure outline in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-2-chloro-phenol amine (144 mg, 1.0 mmol) reacted to give 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 306 (M+H)⁺.

To a solution of 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (340 mg, 1.0 mmol) was added hydrazine (50 μL). After stirring at rt for 1 h, the reaction mixture was poured into ice water (25 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford 2-chloro-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as a pale yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 7.34 (br s, 1H), 7.08 (m, 2H), 2.83 (s, 6H), 2.52 (s, 6); MS (ESI) 302 (M+H)⁺.

EXAMPLE 58 6-(2,4-Dimethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (400 mg, 2.0 mol), 2,4-dimethoxyaniline (305 mg, 2.0 mmol) and hydrazine (200 μL) reacted to give 1,4,5,7-tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.67 (m, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 2.80 (s, 6H), 2.40 (s, 6H); MS (ESI) 312 (M+H)⁺.

EXAMPLE 59 6-(4-Isopropoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (100 mg, 0.5 mol), 2,4-dimethoxyaniline (76 mg, 0.5 mmol) and hydrazine (50 μL) reacted to give 6-(4-Isopropoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.12 (d, 2H), 7.07 (d, 2H), 4.68 (m, 1H), 2.86 (s, 6H), 2.47 (s, 6H), 1.45 (d, 6H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 60 1,4,57-Tetramethyl-6-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 2-methyl-4-(trifluoromethoxy) aniline (191 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give 1,4,5,7-Tetramethyl-6-(4-trifluoromethoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 8.27 (s, 1H), 8.11 (s, 1H), 4.50 (q, 1H), 2.80 (s, 6H), 2.48 (s, 6H), 1.50 (t, 3H); MS (ESI) 298 (M+H)⁺; MS (ESI) 350 (M+H)⁺.

EXAMPLE 61 2-Methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (400 mg, 2.0 mol) and 4-amino-o-cresol (250 mg, 2.0 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 286 (M+1)⁺.

To a solution of 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.32 mmol) in ethanol (5 mL) was added hydrazine (20 μL). After stirring at rt for 1 h, the reaction mixture was poured into ice water (25 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford 2-methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as a pale yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 7.09 (d, 1H), 7.03 (s, 1H), 6.97 (d, 1H), 3.00 (s, 6H), 2.59 (s, 6H), 2.34 (s, 3H); MS (ESI) 282 (M+H)⁺.

EXAMPLE 62 6-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 5-ethoxy-pyrazin-2-yl amine (151 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give 6-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.76 (s, 1H), 6.70 (d, 1H), 4.36 (br m, 4H), 2.83 (s, 6H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 63 3-Methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-3-methyl-phenol (123 mg, 1.0 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as a brown solid: MS (ESI) 306 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (323 mg, 1.0 mmol) and hydrazine (50 μL) reacted to afford 3-methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as brown solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (br s, 1H), 7.08 (m, 2H), 2.83 (s, 6H), 2.52 (s, 6H); MS (ES) 302 (M+H)⁺.

EXAMPLE 64 6-(3-Chloro-4-ethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as outline in Example 57; 80 mg, 0.27 mmol) in 3 mL of dry DMF was added bromoethane (54 mg, 0.5 mmol) and K₂CO₃ powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 302 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-(3-Chloro-4-ethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 7.47 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 4.27 (q, 2H), 2.79 (s, 6H), 2.48 (s, 6H), 1.53 (t, 3H); MS (ESI) 330 (M+H)⁺.

EXAMPLE 65 6-(4-Ethoxy-2-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as outline in Example 63; 56 mg, 0.20 mmol) in 2 mL of dry DMF was added bromoethane (100 μL) and K₂CO₃ powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 314 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-(4-ethoxy-2-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₉, 500 MHz) δ 7.06 (d, 1H), 6.94 (s, 1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s, 3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 66 6-[4-(2-Fluoro-ethoxy)-2-methyl-phenyl]-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

As outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (20 mg) reacted with 1-bromo-2-fluoro ethane (50 μL), in the presence of K₂CO₃ powder (50 mg), to afford 1-{4-acetyl-1-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-2,5-dimethyl-1H-pyrrol-3-yl}-ethanone: MS (ESI) 332 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.94 (s, 1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s, 3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 67 1,4,5,7-Tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine

As outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (Example 52, 20 mg) reacted with 1-bromo-propane (100 μL), in the presence of K₂CO₃ powder (50 mg), to afford 1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 1,4,5,7-Tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.04 (d, 1H), 6.95 (br s, 1H), 6.91 (d, 1H), 4.03 (t, 2H), 2.85 (s, 6H), 2.42 (s, 6H), 1.86 (q, 2H), 1.79 (s, 3H), 1.09 (t, 3H); MS (ESI) 328 (M+H)⁺.

EXAMPLE 68 6-(4-Allyloxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

As in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (Example 52, 20 mg) reacted with allyl bromide (50 μL), in the presence of K₂CO₃ (50 mg), to afford 1-[4-acetyl-1-(4-allyloxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 326 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-allyloxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (20 mg) and hydrazine (50 μL) reacted to give 6-(4-allyloxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.04 (m, 1H), 6.98 (s, 1H), 6.94 (m, 1H), 6.13 (m, 1H), 5.52 (d, 1H), 5.39 (d, 1H), 4.64 (d, 2H), 2.81 (s, 6H), 2.35 (s, 6H), 1.84 (s, 3H); MS (ESI) 322 (M+H)⁺.

EXAMPLE 69 6-(4-ethoxy-3-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as in Example 61) (90 mg, 0.32 mmol) in 3 mL of dry DMF was added bromoethane (108 mg, 1.0 mmol) and K₂CO₃ powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(4-ethoxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 314 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (99 mg, 0.32 mmol) and hydrazine (50 μL) reacted to give 6-(4-ethoxy-3-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CD₃OD, 500 MHz) δ 6.96 (m, 3H), 4.15 (q, 2H), 2.80 (s, 6H), 2.49 (s, 6H), 2.32 (s, 3H), 1.52 (t, 3H); MS (ESI) 310 (M+H)⁺.

EXAMPLE 70 6-(4-Ethoxy-2-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (400 mg, 2.0 mol), 2,4-dimethoxyaniline (305 mg, 2.0 mmol) reacted to give 1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 316 (M+H)⁺.

To a stirring solution of crude 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as above (90 mg, 0.3 mmol) in 5.0 mL of CH₂Cl₂ at 0° C. was added BBr₃ (1.0 M in CH₂Cl₂, 0.9 mL, 0.9 mmol). After 1 h at 0° C., it was warmed to rt and stirred for an additional 2 h before it was quenched with saturated aq. NaHCO₃ solution (5 mL). It was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with dried with MgSO₄, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. This crude material was purified by automated chromatography on silica gel (using 20-50%EtOAc/hexanes gradient) to give the major product 1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as pale yellow oil: MS (ESI) 302 (M+H)⁺; In this reaction, small amount (˜10%) of minor product 1-[4-acetyl-1-(2,4-dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone was also isolated as clear colorless oil: MS (ESI) 288 (M+H)⁺.

Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K₂CO₃ (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 330 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (60 mg) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.06 (d, 1H), 6.66 (m, 2H), 4.05 (q, 2H), 3.86 (s, 3H), 2.84 (s, 6H), 2.41 (s, 6H), 1.25 (t, 3H); MS (ESI) 326 (M+H)⁺

EXAMPLE 71 6-(2,4-diethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(2,4dihydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as in Example 70 (12 mg, 0.4 mmol) reacted with bromoethane (30 μL, excess), in the presence of K₂CO₃ (10 mg), to afford 1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 344 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(2,4-diethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (4 mg) and hydrazine (5 μL) reacted to give 6-(2,4-diethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.03 (d, 1H), 6.67 (s, 1H), 6.64 (d, 1H), 4.15 (q, 1H), 4.04 (q, 1H), 2.89 (br s, 6H), 2.43 (s, 6H), 1.49 (t, 3H, 1.26 (t, 3H); MS (ESI) 340 (M+H)⁺.

EXAMPLE 72 6-(2-ethoxy-4-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a stirring solution of 1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as in Example 70 (1580 mg, 0.5 mmol) in 2.0 mL of dry DMF at rt was added sodium ethanethiolate (80%, Aldrich; 210 mg, 2.0 mmol). After 20 min at rt, it was heated to 120° C. and stirred for an additional 2 h before it was quenched with 1N HCl (5 mL). It was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with dried with MgSO₄, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. This crude material was purified by automated chromatography on silica gel (using an 20-50% EtOAc/hexanes gradient) to give the major product 1-[4-acetyl-1-(2-hydroxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as pale yellow oil: MS (ESI) 302 (M+H)⁺.

Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(2-hydroxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K₂CO₃ (50 mg), to afford 1-[4-acetyl-1-(2-ethoxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 330 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (60 mg) and hydrazine (50 μL) reacted to give 6-(2-ethoxy-4-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.04 (d, 1H), 6.68 (s, 1H), 6.64 (d, 1H), 4.15 (q, 1H), 3.78 (s, 3H), 2.81 (s, 6H), 2.40 (s, 6H), 1.51 (t, 3H); MS (ESI) 326 (M+H)⁺.

EXAMPLE 73 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (300 mg, 1.5 mol) and 4-amino-2.3-xylenol (206 mg, 1.5 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 300 (M+H)⁺.

Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K₂CO₃ (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.92 (d, 1H), 6.86 (d, 1H), 4.14 (q, 2H), 2.83 (s, 6H), 2.36 (s, 6H), 2.28 (s, 3H), 1.72 (s, 3H), 1.52 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 74 6-(4-Ethoxy-2,5-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 481, 1,1,2,2-tetraacetylethane

(200 mg, 1.0 mol) and 4-amino-2,5-dimethylphenol (138 mg, 1.0 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 300 (M+H)⁺.

Utilizing the general procedure outlined in Example 7, 1-[4-acetyl-1-(4-hydroxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K₂CO₃ (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)⁺. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]-pyridazine as an off-white solid: ¹H NMR (CDCl₃, 500 MHz) δ 6.88 (s, 1H), 6.77 (s, 1H), 4.14 (q, 2H), 2.85 (s, 6H), 2.39 (s, 6H), 2.26 (s, 3H), 1.83 (s, 3H, 1.50 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 75 6-(4-Ethoxy-2-fluoro-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 3-fluoro-4-nitrophenol (1.57 g, 10.0 mmol) in 20 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K₂CO₃ powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethyl ether (100 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford 4-ethoxy-2-fluoro-1-nitrobenzene as a pale yellow oil: MS (ESI) 186 (M+H)⁺.

To a solution of 4-ethoxy-2-fluoro-1-nitro benzene (1.0 g, 5.4 mmol) in absolute EtOH (25 mL) at rt was added 250 mg of Pd/C (Aldrich, 10 wt. % on activated carbon), followed by slow addition of hydrazine hydrate (2.5 mL). The resulting reaction mixture was refluxed at 90° C. for 30 min. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford 4-ethoxy-2-fluoro-phenyl amine as a pale yellow oil: MS (ESI) 156 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 4-ethoxy-2-fluoro-phenyl amine (155 mg, 1.0 mmol) and hydrazine (50 μL) reacted to give 6-(4-ethoxy-2-fluoro-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.13 (t, 1H), 6.88 (m, 2H), 4.16 (q, 2H), 2.82 (s, 6H), 2.46 (s, 6H), 1.53 (t, 3H); MS (ESI) 314 (M+H)⁺.

EXAMPLE 76 6-(4-Ethoxy-2-methylsulfanyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 4-Ethoxy-2-fluoro-1-nitro benzene prepared as in Example 75 (185 mg, 1.0 mmol) in 2 mL of dry DMF was added NaSMe (84 mg, 1.20 mmol). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O. The precipitate was filtered, washed with H₂O and dried under vacuum to afford 4-ethoxy-2-methylsulfanyl-1-nitro-benzene as yellow oil: MS (ESI) 211 (M+H)⁺.

To a solution of 4-ethoxy-2-methylsulfanyl-1-nitro-benzene (1.0 g, 5.4 mmol) in absolute EtOH (25 mL) at rt was added 40 mg of Pd/C (Aldrich, 10 wt. % on active carbon), followed by slow addition of hydrazine hydrate (0.5 mL). The resulting reaction mixture was refluxed at 90° C. for 3 h. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford 4-ethoxy-2-methylsulfanyl-phenyl amine as a pale yellow oil: MS (ESI) 184 (M+H)⁺.

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 4-ethoxy-2-methylsulfanyl-phenyl amine (140 mg, 0.8 mmol) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2-methylsulfanyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.05 (d, 1H), 6.88 (s, 1H), 6.82 (d, 1H), 4.16 (q, 2H), 2.81 (s, 6H), 2.42 (s, 6H), 1.53 (t, 3H); MS (ESI) 342 (M+H)⁺.

EXAMPLE 77 6-(4-Ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 3-hydroxymethyl-4-nitro-phenol (510 mg, 3.0 mmol) in 5 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K₂CO₃ powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford (5-ethoxy-2-nitro-phenyl)-methanol as a pale yellow oil: ¹H NMR (CDCl₃, 500 MHz) δ 8.20 (d, 1H), 7.36 (s, 1H), 6.89 (m, 1H), 5.00 (s, 2H), 4.16 (q, 2H), 2.57 (br t, 1H), 1.49 (t, 3H).

To a solution of (5-ethoxy-2-nitro-phenyl)-methanol (592 mg, 3.0 mmol) in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. % on active carbon), followed by slow addition of hydrazine hydrate (1.5 mL). The resulting reaction mixture was refluxed at 90° C. for 1 h. It was then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a pale yellow oil: MS (ESI) 168 (M+H)⁺.

A solution of 1,1,2,2-tetraacetylethane (600 mg, 3.0 mol) and (2-amino-5-ethoxy-phenyl)-methanol (496 mg, 3.0 mmol) was refluxed in EtOH (10 mL)/AcOH (1%) for 14 h. It was cooled to rt, and anhydrous hydrazine (200 μL, 6.3 mmol) was added. After stilling at rt for 1 h, the reaction mixture was poured into ice water (50 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-δ]pyridazin-6-yl)-phenyl]-methanol as a pale yellow solid: 1H NMR (CDCl₃, 500 MHz) δ 7.24 (s, 1H), 6.98 (m, 2H), 4.62 (s, 2H), 4.16 (q, 2H), 2.66 (s, 6H), 2.41 (s, 6H), 1.50 (t, 3H); MS (ESI) 327 (M+H)⁺.

To a solution of [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol (70 mg, 2.3 mmol) in CH₂Cl₂ (10 mL) at rt was added MnO₂ (200 mg, excess). The resulting reaction mixture was stirred at rt for 2 h before if was filtered through Celite, and eluted with CH₂Cl₂ (20 mL×2). The eluant was collected and concentrated in vacuo to afford 5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-δ]pyridazin-6-yl)-benzaldehyde as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 10.56 (s, 1H), 7.71 (s, 1H), 7.40 (d, 1H), 7.20 (d, 1H), 4.28 (q, 2H), 2.86 (s, 6H), 2.45 (s, 6H), 1.58 (t, 3H); MS (ESI) 325 (M+H)⁺.

A suspension of methyltriphenylphosphonium bromide (178 mg, 0.5 mmol) in 3.0 mL of THF at rt was treated with n-BuLi (1.6 M in Hexane, 280 μL, 0.45 mmol) dropwise. After 5 min at rt, it was warmed to 50° C. and stirred for 30 min, and then cooled back to rt to give the in situ generated ylide solution. Part of this reaction solution (2.0 mL) was transferred to another reaction flask containing 5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-δ]pyridazin-6-yl)-benzaldehyde (32 mg, 0.1 mol) and 0.5 mL of THF under N₂ atmosphere. The resulting reaction mixture was stirred at rt for 3 h before it was quenched with H₂O and extracted with diethyl ether (2×10 mL). All organic extracts were combined, dried (MgSO₄), filtered, and concentrated in vacuo to afford crude product as yellow oil. It was purified by preparative TLC plate (20×20 cm, 0.5 mm layer thickness, eluted with 7% CH₂Cl₂/MeOH) to give pure 6-(4-ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-δ]pyridazine as a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.26 (s, 1H), 7.06 (d, 1H), 6.98 (d, 1H), 5.79 (dd, 1H), 5.77 (d, 1H), 5.24 (d, 2H), 4.15 (q, 2H), 2.81 (s, 6H), 2.37 (s, 6H), 1.52 (t, 3H); MS (ESI) 323 (M+H)⁺.

EXAMPLE 78 6-(4-Ethoxy-2-ethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 6-(4-ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine (30 mg, 3.0 mmol) in 3 mL of ethanol was added anhydrous hydrazine (20 μL). The resulting reaction solution was refluxed at 90° C. for 90 min. It was allowed to warm to rt and directly condensed in vacuo to afford 6-(4-Ethoxy-2-ethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.00 (m, 2H), 6.89 (m, 1H), 4.15 (q, 2H), 2.82 (s, 6H), 2.38 (s, 6H), 2.10 (q, 2H), 1.52 (t, 3H), 1.08 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 79 6-(4-Ethoxy-2,6-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in Example 77, 4-nitro-3,5-dimethyl-phenol was converted to 4-ethoxy-2,6-dimethyl-phenylamine in two step. This crude amine was use directly in the next reaction without further purification.

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (308 mg, 1.56 mol), 4-ethoxy-2,6-dimethyl-phenylamine (250 mg, 1.0 mmol) and hydrazine (100 μL) reacted to give 6-(4-ethoxy-2,6-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]-pyridazine as yellow solid: ¹H NM (CDCl₃, 500 MHz) δ 6.81 (s, 1H), 6.75 (s, 1H), 4.04 (q, 2H), 2.82 (s, 6H), 2.44 (s, 6H), 2.47 (s, 3H), 2.35 (s, 6H), 1.79 (s, 3H), 1.88 (t, 3H), ; MS (ESI) 324 (M+H)⁺.

EXAMPLE 80 [5-Ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3.4-d]pyridazin-6-yl)-phenyl]-methanol

To a solution of 3-hydroxymethyl-4-nitro-phenol (510 mg, 3.0 mmol) in 5 mL of dry DMF was added bromoethane (540 mg, 5.0 mmol) and K₂CO₃ powder (500 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H₂O, extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford (5-ethoxy-2-nitro-phenyl)-methanol as a pale yellow oil: ¹H NMR (CDCl₃, 500 MHz ) δ 8.20 (d, 1H), 7.36 (s, 1H), 1), 6.89 (m, 1H), 5.00 (s, 2H), 4.16 (q, 2H), 2.57 (br t, 1H), 1.49 (t, 3H).

To a solution of (5-ethoxy-2-nitro-phenyl)-methane (592 mg, 3.0 mmol) in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. % on activated carbon), followed by slow addition of hydrazine hydrate (1.5 mL). The resulting reaction mixture was refluxed at 90 ° C. for 1h. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a pale yellow oil: MS (ESI) 168 (M+H)⁺.

A solution of 1,1,2,2-tetraacetylethane (600 mg, 3.0 mol) and (2-amino-5-ethoxy-phenyl)-methanol (496 mg, 3.0 mmol) was refluxed in EtOH (10 mL)/AcOH (1%) for 14 h. It was cooled to rt, and anhydrous hydrazine (200 μL, 6.3 mmol) was added. After stirring at rt for 1 h, the reaction mixture was poured into ice water (50 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol as a pale yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.22 (s, 1H), 6.95 (m, 2H), 4.40 (s, 2H), 4.16 (q, 2H), 2.66 (s, 6H), 2.41 (s, 6H), 1.50 (t, 3H); MS (ESI) 326 (M+H)⁺.

EXAMPLE 81 [2-Ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3.4-d]pyridazin-6-yl)-phenyl]-methanol

Utilizing the general procedure outlined in Example 77, 2-hydroxymethyl-4-nitro-phenol was converted to afford (5-amino-2-ethoxy-phenyl)-methanol in two step. This crude amine was use directly in the next reaction without further purification.

Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (308 mg, 1.56 mol), (5-amino-2-ethoxy-phenyl)-methanol (250 mg, 1.0 mmol) and hydrazine (100 μL) reacted to give [2-ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol as yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.24 (s, 1H), 7.08-7.01 (m, 2H), 4.81 (s, 2H), 4.18 (q, 2H), 2.77 (s, 6H), 2.43 (s, 6H), 1.51 (t, 3H); MS (ESI) 326 (M+H)⁺.

EXAMPLE 82 5-Ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehyde

To a solution of [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol (prepared as described in Example 81; 70 mg, 2.3 mmol) in CH₂Cl₂ (10 mL) at rt was added MnO₂ (200 mg, excess). The resulting reaction mixture was stirred at rt for 2 h before if was filtered through Celite, and eluted with CH₂Cl₂ (2×20mL). The eluant was collected and concentrated in vacuo to afford 5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4δ]pyridazin-6-yl)-benzaldehyde as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 10.55 (s, 1H), 7.70 (s, 1H), 7.40 (d, 1H), 7.20 (d, 1H), 4.30 (s, 2H), 2.87 (s, 6H), 2.45 (s, 6H), 1.57 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 83 2-Ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehyde

Utilizing the general procedure outlined in Example 82, [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol (prepared as described in Example 81; 100 mg, 0.3 mmol) reacted with MnO₂ (200 mg, excess) to afford 2-ethoxy-5-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzaldehyde as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 9.20 (s, 1H), 7.57 (s, 1), 7.34 (d, 1H), 7.24 (d, 1H), 4.20 (q, 2H), 2.90 (s, 6H), 2.42 (s, 6H), 1.51 (t, 3H); MS (ESI) 324 (M+H)⁺.

EXAMPLE 84 6-(4-ethoxy-2-nitrophenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4d]pyridazine hydrochloride

To a solution of acetonyl acetone (1.95 mL, 16.5 mmol) in acetic acid (100 mL) was added 4-ethoxy-2-nitroaniline (3.0 g, 16.5 mmol) and the red mixture heated at reflux overnight. After cooling to rt, the now black solution was poured into water and extracted with EtOAc (2×200mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to an oil. Purification by flash chromatography (10% EtOAc/hexanes) gave 2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as a red oil: ¹H NMR (CDCl₃, 500 MHz) δ 7.46 (d, 1H), 7.27 (t, 1H), 7.19 (dd, 1H), 5.91 (s, 2H), 4.15 (q, 1H), 1.96 (s, 6H), 1.50 (t, 3H); MS (ESI) 261 (M+H)⁺.

To a solution of 2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole (3.10 g, 11.9 mmol) in CH₂Cl₂ (80 mL) at 0° C. was added acetyl chloride (2.13 mL, 30 mmol) followed by dropwise addition of tin(IV) chloride (3.51mL, 30 mmol). The solution was allowed to warm to rt overnight followed by heating at reflux for an addition 24 hours. After cooling to rt, the reaction was diluted with 0.25 M NaOH, extracted with EtOAc, the organic layer washed with brine, dried over MgSO₄, filtered, concentrated in vacuo, and purified by flash chromatography (20-75% EtOAc/hexanes) to give 3,4-diacetyl-2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as a green solid (MS (ESI) 345 (M+H)⁺; the major product being monoacylation). The solid was taken up in ethanol (10 mL), an excess of hydrazine (0.1 mL) added, and the solution heated at 50° C. After 3 hours, the reaction was poured over ice, filtered, taken up in hot ether, precipitated with HCl in ether, and filtered to give 6-(4-ethoxy-2-nitrophenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine hydrochloride as a tan solid: ¹H NMR (DMSO-d₆, 500 MHz) δ 7.93 (d, 1H), 7.68-7.61 (m, 2H), 4.29 (q, 1H), 3.02 (br s, 3H), 2.82 (br s, 3H), 2.46 (s, 6H), 1.42 (t, 3H); MS (ESI) 341 (M+H)⁺.

EXAMPLE 85 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

To a slurry of NaH (2.6 g, 66 mmol, 60% dispersion in mineral oil) and THF (200 mL) at 0° C. was added ethyl acetoacetate (7.8 mL, 60 mmol) dropwise. After 15 min, α-chloroacetone (5.2 mL, 66 mmol) was added and the resulting solution allowed to warm to rt over 12 h. The reaction mixture was partitioned between MTBE and water, the water layer extracted with MTBE (2×50 mL), and the combined extracts dried (MgSO₄), and concentrated under reduced pressure to afford, after automated chromatography on silica gel (using an EtOAc/hexanes gradient), ethyl 2-acetyl-4-oxopentanoate as a colorless oil.

Ethyl 2-acetyl-4-oxopentanoate (6.37 g, 34.2 mmol) was dissolved in 20 mL of EtOH. p-Phenetidine (4.70 g, 34.2 mmol) was added as well as several drops of AcOH and heated at reflux for 15 h. The reaction mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting brown oil was dissolved in CH₂Cl₂ (20 mL) and washed with saturated aqueous NaHCO₃ (3×50 mL) dried (MgSO₄) and concentrated. The resulting crude ethyl 1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate was taken on without further purification. MS (ESI) 288 (M+H)⁺.

In an oven-dried flask, ethyl 1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (9.32 g, 32.5 mmol) combined with toluene (100 mL), acetyl chloride (2.8 mL, 39.3 mmol), and SnCl₄ (4.67 mL, 29.3 mmol). The reaction mixture was stirred at rt for 4 h. The reaction was quenched by the addition of 1N NaOH (added until pH 12 was reached) and the aqueous layer extracted with CH₂Cl₂ (2×200 mL) and Et₂O (2×100 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The resulting crude (ethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate) was of sufficient purity for further reactions. MS (ESI) 330 (M+H)⁺.

A solution of ethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (7.50 g, 22.8 mmol) and EtOH (75 mL) was placed in a resealable reaction vessel. Hydrazine (2 mL, 64 mmol) and AcOH (˜1 mL) were added, the tube closed, and heated to 80° C. for 12 h. The resulting slurry was allowed to cool to rt and poured into ice water (50 mL). The resulting white solid (6-(4-ethoxyphenyl)4,5,7-trimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one) was filtered and dried under vacuum for 8 h. MS (ESI) 298 (M+H)⁺.

A solution of POCl₃ (15 mL) and 6-(4-ethoxyphenyl)4,5,7-trimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (1.5 g) were combined and heated at reflux for 48 h. The reaction mixture was allowed to cool to rt, and was quenched by the careful addition of water (50 mL) followed by a saturated aqueous solution NaHCO₃ (50 mL). The reaction mixture was extracted with CH₂Cl₂ (5×50 mL), and the combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure to yield 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow/green solid. MS (ESI) 316 (M+H)⁺.

To a Personal Chemistry Microwave Synthesizer microwave vial was combined 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (200 mg, 0.64 mmol), MeNH₂ (1 mL, 40% in H₂O), and EtOH (1 mL). The vial was sealed and heated at 120° C. for 12 min. The reaction mixture was poured into water to afford crude 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine. Purification by reverse phase preparative HPLC using a YMC CombiPrep Pro C₁₈20×100 column (Gradient: 5%-100% Acetonitrile in a H₂O+0.1% TFA solution over 10 min, retention time: 6.1 min) afforded pure 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine as a colorless solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.05-7.12 (m, 4H), 4.16 (q, 2H), 3.20 (s, 3H), 2.69 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.51 (t, 3H); MS (ESI) 311 (M+H)⁺.

EXAMPLE 86 6-(4-ethoxyphenyl)-N,N,4,5,7-pentamethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine

Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and Me₂N (1 mL, 40% solution in H₂O) reacted to give 6-(4-ethoxyphenyl)-N,N,4,5,7-pentamethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine: ¹H NMR (CDCl₃, 500 MHz) δ 7.06-7.15 (m, 4H), 4.15 (q, 2H), 3.08 (s, 6H), 2.78 (s, 3H), 2.50 (s, 2H), 2.44 (s, 2H), 1.51-1.52 (s, 3H); MS (ESI) 325 (M+H)⁺.

EXAMPLE 87 6-(3,5-dibromo-4-ethoxyphenyl)-1-aminomethyl-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the procedure outlined in Example 85, ethyl 2-acetyl-4-oxopentanoate (6.37 g, 34.2 mmol) was dissolved in 20 mL of EtOH. 2,6-dibromo-4-aminophenol (11.6g, 34.2mmol) were reacted to afford ethyl 1-(3,5-dibromo-4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate was taken on without further purification. MS (ESI) 418 (M+H)⁺.

Crude ethyl 1-(3,5-dibromo-4-hydroxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate was mixed with Cs₂CO₃ (11.4 g, 35 mmol), bromoethane (7.50 g, 70.0 mmol), and MeCN (150 mL) and heated at 50 ° C. for 4 hr. Standard aqueous workup afforded, after purification on silica gel (utilizing an ethyl acetate/hexanes gradient) ethyl 1-(3,5-dibromo-4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate as a reddish solid. MS (ESI) 446 (M+H)⁺. This compound was processed as in example 85 to afford 6-(3,5-dibromo-4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine as a colorless solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.41 (s, 2H), 4.19 (q, 2H), 3.13 (s, 3H), 2.62 (s, 3H), 2.59 (s, 3H), 2.40 (s, 3H), 1.54 (t, 3H); MS (ESI) 469 (M+H)⁺.

EXAMPLE 88 6-(4-ethoxyphenyl)-1-(4-methoxyphenyl)amino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and p-anisidine (0.40 mg, 0.32 mmol) reacted to give 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: ¹H NMR (CDCl₃, 500 MHz) δ 7.32 (d, 2H), 7.08 (d, 2H), 7.06 (d, 2H), 6.91 (d, 2H), 4.12 (q, 2H), 3.81 (s, 3H), 2.69 (s, 3H), 2.55 (s, 3H), 1.50 (t, 3H); MS (ESI) 403 (M+H)⁺.

EXAMPLE 89 6-(4-ethoxyphenyl)-1-aminophenyl-4.5.7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and aniline (0.36 mg, 0.32 mmol) reacted to give 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: ¹H NMR (CDCl₃, 500 MHz) δ 7.33-7.36 (m, 3H), 6.65-7.13 (m, 6H), 4.14 (q, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H) 1.52 (t, 3H); MS (ESI) 403 (M+H)⁺.

EXAMPLE 90 6-(4-ethoxyphenyl)-1-(4-methylphenyl)amino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and 4-methylaniline (0.40 mg, 0.32 mmol) reacted to give 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: ¹H NMR (CDCl₃, 500 MHz) δ 7.50 (d, 2), 7.17 (d, 2H), 7.16 (d, 2H), 6.99 (d, 2H), 4.16 (q, 2H), 2.81 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.52 (t, 3H); MS (ESI) 423 (M+H)⁺.

EXAMPLES 91-367

Example 91-367 were synthesized in library mode. 1-Chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (50 mg per vessel) or 1-Chloro-6-(2-methoxy-4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (prepared as in example 85 utilizing 2-methoxy-4-ethoxy aniline) (50 mg per vessel), and polystyrene resin-bound N-methylmorpholine (1.1 eq.) were dry loaded into reaction vessels. Amines (2 eq.) in pyridine (1 mL) was added to the vessels. The vessels were capped and sealed. The reactions were heated to 100 ° C. and agitated overnight. Additional polystyrene resin-bound N-methylmorpholine (2 eq.), polystyrene resin-bound chloroformate (2 eq.), and chloroform (4 mL) were added. The resulting suspension was agitated at 50 ° C. overnight. The reaction solutions were collected by filtration, concentrated and dried in GeneVac. The products were analyzed by LCMS. MS Example Name Structure (ESI) Example 91 6-(4-ethoxy-2- methoxyphenyl)-N-(1H- indol-5-ylmethyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

457 Example 92 N-benzyl-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

418 Example 93 N-(1,3-dihydro-2- benzofuran-5-yl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1-amine

446 Example 94 1-(4-{[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]amino}phenyl)imidazolidin- 2-one

488 Example 95 6-(4-ethoxy-2- methoxyphenyl)-N-(3- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d[pyridazin-1-amine

434 Example 96 6-(4-ethoxy-2- methoxyphenyl)-N-(3- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

446 Example 97 N-(3,5-dimethoxyphenyl)- 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

464 Example 98 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-phenyl-6H- pyrrolo[3,4-d]pyridazin-1-amine

404 Example 99 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(3-pyridin-3- ylpropyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

447 Example 100 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-pyridin-2- ylethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

433 Example 101 6-(4-ethoxy-2- methoxyphenyl)-N- isopropyl-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

369 Example 102 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[4- (methylthio)phenyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

450 Example 103 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(4- methylbenzyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

432 Example 104 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(pyridin-3- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

419 Example 105 6-(4-ethoxy-2- methoxyphenyl)-N- (2,4,5,6,7,8- hexahydrocyclohepta[c]pyrazol-3-ylmethyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

476 Example 106 4-(2-{[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]amino}ethyl)phenol

448 Example 107 N-(3-{[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]amino}phenyl)acetamide

461 Example 108 6-(4-ethoxy-2- methoxyphenyl)-N-(3- fluoro-4-methylphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

436 Example 109 1-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]piperidine- 4-carboxamide

439 Example 110 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(pyridin-2- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

419 Example 111 N-butyl-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

384 Example 112 N-(3,4-dimethoxybenzyl)- 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

478 Example 113 N-(cyclohexylmethyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

424 Example 114 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N- (tetrahydrofuran-2- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

412 Example 115 N-(2,3-dihydro-1H-inden- 1-yl)-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

444 Example 116 6-(4-ethoxy-2- methoxyphenyl)-N-(4- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

434 Example 117 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2- methylbenzyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

432 Example 118 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(3- phenylpropyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

446 Example 119 N-(2,3-dihydro-1H-inden- 2-ylmethyl)-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

458 Example 120 6-(4-ethoxy-2- methoxyphenyl)-N-1H- indazol-6-yl-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

444 Example 121 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(1- phenylethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

432 Example 122 6-(4-ethoxyphenyl)-N-1H- indol-5-yl-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

413 Example 123 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-methyl-1,3- benzothiazol-6-yl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

475 Example 124 N-cyclopentyl-6-(4-ethoxy- 2-methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

396 Example 125 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2- phenylpropyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

446 Example 126 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(4- phenylbutyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

460 Example 127 6-(4-ethoxy-2- methoxyphenyl)-N-[(1- ethyl-1H-pyrazol-4- yl)methyl]-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

436 Example 128 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(5,6,7,8- tetrahydro-1,8- naphthyridin-2-ylmethyl)- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

444 Example 129 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[2-(tetrahydro- 2H-pyran-2-yl)ethyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

440 Example 130 6-(4-ethoxy-2- methoxyphenyl)-N-(3- methoxybenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

448 Example 131 N-(3,4-dimethoxyphenyl)- 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

464 Example 132 6-(4-ethoxy-2- methoxyphenyl)-N-2H- indazol-5-yl-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

444 Example 133 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- methylbenzyl)-6H- pyrrolo[3,4-d]pyrldazin-1- amine

432 Example 134 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(spiro[2.5]oct- 1-ylmethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

450 Example 135 N-(2,2-dimethoxyethyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

416 Example 136 6-(4-ethoxy-2- methoxyphenyl)-N-(2- furylmethyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

407 Example 137 6-(4-ethoxy-2- methoxyphenyl)-N-1H- indol-5-yl-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

443 Example 138 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(1- methylpiperidin-4- yl)methyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

439 Example 139 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(1- phenylpiperidin-4-yl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

487 Example 140 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2- phenylethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

432 Example 141 1-(4-{[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]amino}phenyl)-3- methylimidazolidin-2-one

502 Example 142 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[1-methyl-2- (1H-1,2,4-triazol-1- yl)ethyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

437 Example 143 N-(2-ethoxybenzyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

462 Example 144 4-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-2,3,4,5- tetrahydro-1,4-benzoxazepine

460 Example 145 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[2-(1H-pyrazol- 1-yl)ethyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

422 Example 146 N-(4-chlorobenzyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

452 Example 147 6-(4-ethoxyphenyl)-N-1H- indazol-5-yl-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

413 Example 148 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[3- (trifluoromethyl)benzyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

486 Example 149 (3-{[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]amino}phenyl)methanol

434 Example 150 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-methyl-1,3- benzothiazol-5-yl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

475 Example 151 N-(3-chlorobenzyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

422 Example 152 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(1- methylpyrrolidin-3- yl)methyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

425 Example 153 6-(4-ethoxy-2- methoxyphenyl)-N-[2-(3- methoxyphenyl)ethyl]- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

462 Example 154 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(1-methyl-1H- pyrazol-4-yl)methyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

422 Example 155 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(pyrazolo[1,5- a]pyridin-7-ylmethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

458 Example 156 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(4- phenoxyphenyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

496 Example 157 N′-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-N,N- dimethylbenzene-1,4- diamine

447 Example 158 6-(4-ethoxy-2- methoxyphenyl)-N-(3- isopropoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

462 Example 159 6-(4-ethoxy-2- methoxyphenyl)-N-(2- methoxyethyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

385 Example 160 N-(3-chloro-4- methylphenyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

452 Example 161 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[2-(1- methylpyrrolidin-2- yl)ethyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

439 Example 162 N-[2-(3- chlorophenyl)ethyl]-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrroro[3,4-d]pyridazin-1- amine

466 Example 163 N-(2,3-dihydro-1,4- benzodioxin-6-yl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

462 Example 164 N-cyclobutyl-6-(4-ethoxy- 2-methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

381 Example 165 N-(3,4-dihydro-1H- isochromen-1-ylmethyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

474 Example 166 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(3-morpholin- 4-ylpropyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

455 Example 167 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-pyrazin-2- ylethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

434 Example 168 7-chloro-4-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-2,3,4,5- tetrahydro-1,4- benzoxazepine

494 Example 169 6-(4-ethoxy-2- methoxyphenyl)-N-[2-(4- methoxyphenyl)ethyl]- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

462 Example 170 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[3- (methylthio)phenyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

450 Example 171 N-(1-benzylpiperidin-4-yl)- 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

501 Example 172 6-(4-ethoxy-2- methoxyphenyl)-N-(3- fluorobenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

436 Example 173 N-cyclopropyl-6-(4-ethoxy- 2-methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

367 Example 174 (3aR,9bR)-2-(6-(4-ethoxy- 2-methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]- 2,3,3a,4,5,9b-hexahydro- 1H-benzote]e]isoindole

484 Example 175 6-(4-ethoxy-2- methoxyphenyl)-N-(3- ethylphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

432 Example 176 N-(3,5-dimethylphenyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

432 Example 177 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-morpholin- 4-ylethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

441 Example 178 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-(4-phenyl-1,4- diazepan-1-yl)-6H- pyrrolo[3,4-d]pyridazine

487 Example 179 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[4- (trifluoromethoxy)phenyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

487 Example 180 6-(4-ethoxy-2- methoxyphenyl)-N-(2- methoxybenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

448 Example 181 3-benzyl-7-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-5,6,7,8- tetrahydroimidazo[1,2- a]pyrazine

524 Example 182 N′-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-N,N- diethylpropane-1,3-diamine

441 Example 183 6-(4-ethoxy-2- methoxyphenyl)-N-(3- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

448 Example 184 7-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-2- (trifluoromethyl)-5,6,7,8- tetrahydroimidazo[1,2- a]pyrazine

502 Example 185 N-(3-chloro-4- methoxyphenyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

468 Example 186 1-[4-(2,3-dihydro-1,4- benzodioxin-5- yl)piperazin-1-yl]-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

531 Example 187 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(6- methylpyridin-2-yl)methyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

433 Example 188 6-(4-ethoxy-2- methoxyphenyl)-N-(4- ethylphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

432 Example 189 1-azetidin-1-yl-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

367 Example 190 N-(3,4-dimethylphenyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

432 Example 191 N-(3,4-difluorobenzyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

454 Example 192 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N- (tetrahydrofuran-2- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

381 Example 193 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-morpholin-4-yl- 6H-pyrrolo[3,4-d]pyridazine

397 Example 194 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-[4- (trifluoromethyl)phenyl]ethyl}-6H-pyrrolo[3,4- d]pyridazin-1-amine

500 Example 195 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(octahydro-2H- quinolizin-1-ylmethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

479 Example 196 N-(3-chlorobenzyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

452 Example 197 6-(4-ethoxy-2- methoxyphenyl)-N-[2-(2- methoxyphenyl)ethyl]- 4,5,7-trimethyl-6H- pyrroloE3,4-d]pyridazin-1- amine

462 Example 198 N-(3-bromo-4- methylphenyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

496 Example 199 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[3-(2- methylpiperidin-1- yl)propyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

467 Example 200 2-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-2,3,4,9- tetrahydro-1H-beta- carboline

483 Example 201 N-(2,3-dihydro-1H-inden- 1-yl)-6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

414 Example 202 N-(sec-butyl)-6-(4-ethoxy- 2-methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

384 Example 203 N-(3,4-dichlorobenzyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

486 Example 204 3-{4-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]piperazin- 1-yl}phenyl

489 Example 205 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-[(1S,5R)-1,3,3- trimethyl-6- azabicyclo[3.2.1]oct-6-yl]- 6H-pyrrolo[3,4-d]pyridazine

464 Example 206 N-[3-(benzyloxy)phenyl]-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

510 Example 207 6-(4-ethoxyphenyl)-N-1H- indazol-5-yl-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-aminium chloride

450 Example 208 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(1-piperidin-1- ylcyolohexyl)methyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

507 Example 209 N-butyl-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

353 Example 210 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(quinolin-8- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

439 Example 211 6-(4-ethoxy-2- methoxyphenyl)-N-(4- isopropylphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

446 Example 212 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[4- (trifluoromethyl)benzyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

486 Example 213 6-(4-ethoxyphenyl)-N-[(1- ethyl-1H-pyrazol-4- yl)methyl]-4,5,7-trimethyl- 6H-pyrroto[3,4-d]pyridazin- 1-amine

406 Example 214 N-[2-(4- chlorophenyl)ethyl]-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

466 Example 215 N-(4-chlorobenzyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

422 Example 216 1-[4-(2,5- dimethylphenyl)piperazin- 1-yl]-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

501 Example 217 1-(4-benzylpiperazin-1-yl)- 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

487 Example 218 6-(4-ethoxyphenyl)-N- isopropyl-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

339 Example 219 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[2-(tetrahydro- 2H-pyran-2-yl)ethyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

410 Example 220 N-(3-chloro-4-morpholin- 4-ylphenyl)-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

523 Example 221 N-[(3-cyclopropyl-1H- pyrazol-5-yl)methyl]-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

418 Example 222 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(2-phenyl-1,3- thiazol-4-yl)methyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

501 Example 223 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[(1-methyl-1H- pyrazol-4-yl)methyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

391 Example 224 6-(4-ethoxy-2- methoxyphenyl)-N- (isoquinolin-5-ylmethyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

469 Example 225 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-[2- (phenoxymethyl)morpholin- 4-yl]-6H-pyrrolo[3,4- d]pyridazine

504 Example 226 6-(4-ethoxyphenyl)-N-(1H- indol-4-ylmethyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

427 Example 227 N-(2,2-diphenylethyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

508 Example 228 N-(4-tert-butylphenyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

460 Example 229 N′-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-N,N- dimethylethane-1,2- diamine

399 Example 230 6-(4-ethoxyphenyl)-N-[2- (3-methoxyphenyl)ethyl]- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

432 Example 231 6-(4-ethoxyphenyl)-N-(2- methoxybenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

418 Example 232 2-(2-{[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]amino}ethyl)quinazolin- 4(3H)-one

500 Example 233 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

327 Example 234 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-(4-pyridin-2- ylpiperazin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

474 Example 235 6-(4-ethoxy-2- methoxyphenyl)-N-(4- fluorobenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

436 Example 236 1-[(2R,6S)-2,6- dimethylmorpholin-4-yl]-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

426 Example 237 1-(3,5-dimethylpiperidin-1- yl)-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

424 Example 238 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(1- naphthylmethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

468 Example 239 4-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1- yl]piperazine-1- carbaldehyde

425 Example 240 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[(6- methylpyridin-2-yl)methyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

403 Example 241 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(2- methylbutyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

368 Example 242 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(pyridin-4- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

388 Example 243 (3aR,9bR)-2-[6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- 2,3,3a,4,5,9b-hexahydro- 1H-benzo[e]isolndole

454 Example 244 1-{4-[2-(4- chlorophenyl)ethyl]piperidin-1-yl}-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

534 Example 245 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[(1-morpholin- 4-ylcyclohexyl)methyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

509 Example 246 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-(4- methylpiperidin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

410 Example 247 N-(2,4-dichlorobenzyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

486 Example 248 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(3-pyridin-3- ylpropyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

417 Example 249 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-(4- phenylpiperazin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

473 Example 250 ethyl 1-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]piperidine- 4-carboxylate

468 Example 251 N-(2,3-dihydro-1H-inden- 5-yl)-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

444 Example 252 6-(4-ethoxy-2- methoxyphenyl)-1-[4-(2- fluorophenyl)piperazin-1- yl]-4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

491 Example 253 6-(4-ethoxyphenyl)-N-(4- fluorobenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

405 Example 254 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-[3-[methyl-4-(4- methylphenyl)piperazin-1- yl]-6H-pyrrolo[3,4- d]pyridazine

501 Example 255 6-(4-ethoxy-2- methoxyphenyl)-1-[4-(2- methoxyphenyl)piperazin- 1-yl]-4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

503 Example 256 2-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-1,2,3,4- tetrahydroisoquinoline

444 Example 257 1-(4-{4-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]piperazin- 1-yl}phenyl)ethanone

515 Example 258 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(4- methylcyclohexyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

424 Example 259 N-(3,3-diphenylpropyl)-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

522 Example 260 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[2-(1,3-thiazol- 2-yl)ethyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

409 Example 261 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-[2-(3- phenylpyrrolidin-1- yl)ethyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

501 Example 262 6-(4-ethoxy-2- methoxyphenyl)-N- isobutyl-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

384 Example 263 1-[4-(1,3-benzodioxol-5- ylmethyl)piperazin-1-yl]-6- (4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

531 Example 264 4-(4-chlorophenyl)-1-[6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]piperidin-4-ol

522 Example 265 6-(4-ethoxy-2- methoxyphenyl)-1-[4-(4- fluorophenyl)piperazin-1- yl]-4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

491 Example 266 1-[4-(4- chlorophenyl)piperazin-1- yl]-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

507 Example 267 6-(4-ethoxyphenyl)-N-[2- (4-methoxyphenyl)ethyl]- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

432 Example 268 N-(1H-benzimidazol-2- ylmethyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

428 Example 269 1-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-4-[3- (trifluoromethyl)phenyl]piperidin-4-ol

556 Example 270 ethyl 1-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]piperidine- 3-carboxylate

468 Example 271 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(pyridin-3- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

388 Example 272 N-(3,4-difluorobenzyl)-6- (4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

423 Example 273 6-(4-ethoxyphenyl)-N-(3- fluorobenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

405 Example 274 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-[3-methyl-4-(3- methylphenyl)piperazin-1- yl]-6H-pyrrolo[3,4- d]pyridazine

501 Example 275 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-{4-[(2E)-3- phenylprop-2-en-1- yl]piperazin-1-yl}-6H- pyrrolo[3,4-d]pyridazine

513 Example 276 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(pyrazolo[1,5- a]pyridin-7-ylmethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

428 Example 277 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(pyrazolo[1,5- a]pyridin-7-ylmethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

428 Example 278 N-[2-(4- chlorophenyl)ethyl]-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

436 Example 279 1-[4-(3,4- dimethylphenyl)piperazin- 1-yl]-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

501 Example 280 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(1- phenylethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

402 Example 281 N-[2-(2,4- dichlorophenyl)ethyl]-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

500 Example 282 N-(3,4-dimethoxyphenyl)- 6-(4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

434 Example 283 2-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-2,3,4,9-tetrahydro-1H- beta-carboline

453 Example 284 8-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-N-(2-pyrrolidin-1- ylethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

425 Example 285 6-(4-ethoxyphenyl)-N- isobutyl-4,5,7-trimethyl- 6H-pyrrolo[3,4-d]pylidazin- 1-amine

353 Example 286 8-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-1,4-dioxa- 8-azaspiro[4.5]decane

454 Example 287 2-({[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]amino}methyl)quinazolin- 4(3H)-one

456 Example 288 1-[4-(2,4- dimethylphenyl)piperazin- 1-yl]-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

501 Example 289 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(2- phenylethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

402 Example 290 1-(3,3-diphenylpyrrolidin- 1-yl)-6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

504 Example 291 N-{1-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]pyrrolidin-3-yl}acetamide 409 Example 292 6-(4-ethoxy-2- methoxyphenyl)-1-(4- ethylpiperazin-1-yl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

425 Example 293 N-cyclopentyl-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

365 Example 294 6-(4-ethoxy-2- methoxyphenyl)-1,5,7- trimethyl-4-piperidin-1-yl- 6H-pyrrolo[3,4- d]pyridazine

396 Example 295 N-(1-benzothien-2- ylmethyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

444 Example 296 N′-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-N,N- diethylethane-1,2-diamine

427 Example 297 1′-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-yl]-1,4′- bipiperidine

479 Example 298 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(3- phenylpropyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

416 Example 299 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(2-morpholin- 4-ylethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

411 Example 300 N′-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-N,N-diethylethane-1,2- diamine

397 Example 301 N-(1,3-dihydro-2- benzofuran-5-yl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

416 Example 302 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(1,2,3,4- tetrahydronaphthalen-1- yl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

428 Example 303 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[2- (trifluoromethyl)benzyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

455 Example 304 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[(2-phenyl-1,3- thiazol-4-yl)methyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

471 Example 305 2-(2-{[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]amino}ethyl)quinazolin- 4(3H)-one

470 Example 306 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(4- phenylbutyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

430 Example 307 6-(4-ethoxyphenyl)- N4,5,7-tetramethyl-N-(2- pyridin-2-ylethyl)-6H- pyrrolo[3,4-d]pyridazin-1- amine

417 Example 308 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-pyrrolidin-1-yl- 6H-pyrrolo[3,4- d]pyridazine

351 Example 309 1-[6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]ethylpiperidine-3- carboxamide

495 Example 310 N-(2,3- dimethylcyclohexyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

408 Example 311 6-(4-ethoxyphenyl)-N-(2- methoxyethyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

355 Example 312 N-(2,3-dihydro-1H-inden- 5-yl)-6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

414 Example 313 N-(2,4-dichlorobenzyl)-6- (4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

456 Example 314 N-1,3-benzodioxol-5-yl-6- (4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

417 Example 315 6-(4-ethoxyphenyl)-N-(4- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

404 Example 316 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-piperidin-1-yl- 6H-pyrrolo[3,4- d]pyridazine

365 Example 317 N-(1,3-dimethylbutyl)-6-(4- ethoxy-2-methoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

412 Example 318 1-[4-(3,4- dichlorophenyl)piperazin- 1-yl]-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

541 Example 319 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[4- (methylthio)phenyl]-6H- pyrrolo[3,4-d]pyridazin-1- amine

420 Example 320 6-(4-ethoxyphenyl)-N-(3- methoxybenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

418 Example 321 1-(4-cyclohexylpiperazin- 1-yl)-6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

479 Example 322 1-(4-benzylpiperazin-1-yl)- 6-(4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

457 Example 323 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-(4- phenylazepan-1-yl)-6H- pyrrolo[3,4-d]pyridazine

456 Example 324 6-(4-ethoxyphenyl)-N- (isoquinolin-8-ylmethyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

439 Example 325 N-(2-ethoxybenzyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

432 Example 326 N-(1,3-dimethylbutyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

382 Example 327 6-(4-ethoxyphenyl)-N-(3- fluoro-4-methylphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

405 Example 328 N-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-1H-1,2,3-benzotriazol- 5-amine

414 Example 329 6-(4-ethoxyphenyl)-N-(4- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

404 Example 330 N-(3,3-diphenylpropyl)-6- (4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

492 Example 331 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-(4- methylpiperidin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

380 Example 332 2-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-1,2,3,4- tetrahydroisoquinoline

414 Example 333 N′-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-N,N-dimethylethane- 1,2-diamine

368 Example 334 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-[(1S,5R)-1,3,3- trimethyl-6- azabicyclo[3.2.1]oct-6-yl]- 6H-pyrrolo[3,4- d]pyridazine

434 Example 335 1′-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-1,4′-bipiperidine

449 Example 336 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-(4- phenylpiperazin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

443 Example 337 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-(4-pyridin-2- ylpiperazin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

444 Example 338 1-[4-(1,3-benzodioxol-5- ylmethyl)piperazin-1-yl]-6- (4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

501 Example 339 6-(4-ethoxyphenyl)-N-(4- isopropylphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

416 Example 340 1-[4-(3,4- dimethylphenyl)piperazin- 1-yl]-6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

471 Example 341 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[3-(2- methylpiperidin-1- yl)propyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

437 Example 342 N-(1-benzylpiperidin-4-yl)- 6-(4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

471 Example 343 N-(3-chloro-4-morpholin- 4-ylphenyl)-6-(4- ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

493 Example 344 6-(4-ethoxyphenyl)-1-[4- (4-fluorophenyl)piperazin- 1-yl]-4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

461 Example 345 1-(3,5-dimethylpiperidin-1- yl)-6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

394 Example 346 6-(4-ethoxyphenyl)-N-(4- methoxybenzyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

418 Example 347 6-(4-ethoxyphenyl)-1-[4-(2- methoxyphenyl)piperazin- 1-yl]-4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

473 Example 348 N′-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-N,N-diethylpropane- 1,3-diamine

411 Example 349 6-(4-ethoxyphenyl)-1-[4- (2-fluorophenyl)piperazin- 1-yl]-4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

461 Example 350 N-benzyl-6-(4- ethoxyphenyl)-N,4,5,7- tetramethyl-6H- pyrrolo[3,4-d]pyridazin-1- amine

402 Example 351 1-{4-[2-(4- chlorophenyl)ethyl]piperidin- 1-yl]-6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

504 Example 352 N˜4˜-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-N˜1˜,N˜1˜- diethylpentane-1,4- diamine

439 Example 353 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[4- (trifluoromethyl)benzyl]- 6H-pyrrolo[3,4-d]pyridazin- 1-amine

455 Example 354 1-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-4-[3- (trifluoromethyl)phenyl]piperidin-4-ol

526 Example 355 N-[3,5- bis(trifluoromethyl)benzyl]- 6-(4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

523 Example 356 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-[2-(1- methylpyrrolidin-2- yl)ethyl]-6H-pyrrolo[3,4- d]pyridazin-1-amine

409 Example 357 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-morpholin-4-yl- 6H-pyrrolo[3,4- d]pyridazine

367 Example 358 6-(4-ethoxyphenyl)-1-[4- (2-furoyl)piperazin-1-yl]- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazine

461 Example 359 4-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]piperazine-1- carbadehyde

394 Example 360 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-(4- methylpiperazin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

381 Example 361 1-[(2R,6S)-2,6- dimethylmorpholin-4-yl]-6- (4-ethoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazine

396 Example 362 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(pyridin-2- ylmethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

388 Example 363 6-(4-ethoxyphenyl)-4,5,7- trimethyl-N-(2-pyrrolidin-1- ylethyl)-6H-pyrrolo[3,4- d]pyridazin-1-amine

395 Example 364 1-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-N,N-diethylpiperidine-3- carboxamide

465 Example 365 N-[6-(4-ethoxyphenyl)- 4,5,7-trimethyl-6H- pyrrolo[3,4-d]pyridazin-1- yl]-N-ethyl-N′,N′- dimethylethane-1,2-diamine

397 Example 366 6-(4-ethoxyphenyl)-1,5,7- trimethyl-4-(4- methylpiperazin-1-yl)-6H- pyrrolo[3,4-d]pyridazine

381 Example 367 6-(4-ethoxy-2- methoxyphenyl)-4,5,7- trimethyl-6H-pyrrolo[3,4- d]pyridazin-1-amine

327

EXAMPLE 368 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and hydrazine (0.10 mL, 0.32mmol) reacted to give 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: ¹H NMR (CDCl₃, 500 MHz) δ 7.03-7.11 (m, 4H), 4.12 (q, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 1.69 (s, 2H), 1.50 (t, 3H); MS (ESI) 312 (M+H)⁺.

EXAMPLE 369 6-(4-ethoxyphenyl)-1-methoxy-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

A solution of 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (EXAMPLE 85) (100 mg, 0.32 mmol) and MeOH (5 mL) was treated with a solution of NaOMe (freshly prepared from MeOH (5 mL) and sodium metal (22 mg, 0.96 mmol)). The resulting mixture was placed in a resealable reaction vessel and heated at 100° C. for 12 h. The reaction was allowed to cool to rt, and poured into ice water (100 mL) to give 6-(4-ethoxyphenyl)-1-methoxy-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: ¹H NMR (CDCl₃, 500 MHz) δ 7.11-7.25 (m, 4H), 4.16 (q, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 1.43-1.46 (t, 3H); MS (ESI) 312 (M+H)⁺.

EXAMPLE 370 6 (4-ethoxyphenyl)-2,4,5,7-tetramethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

A solution of ethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (prepared as in EXAMPLE 85) (70 mg, 0.20 mmol) and MeOH (5 mL) in a resealable reaction vessel was mixed with methylhydrazine (0.032 mL, 0.60 mmol) and AcOH (˜3 drops). The vessel was sealed and heated at 70° C. for 12 h. The resulting slurry was allowed to cool to rt and poured into ice water (50 mL). The resulting white solid was filtered and dried under vacuum for 8 h to give 6-(4-ethoxyphenyl)-2,4,5,7-tetramethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one: ¹H NMR (CDCl₃, 500 MHz) δ 7.00-7.26 (m, 4H), 4.10 (q, 2H), 3.71 (s, 3H), 2.49 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 1.48 (t, 3H); MS (ESI) 312 (M+H)⁺.

EXAMPLE 371 6-(4-ethoxyphenyl)-5-phenyl-1,4,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine

To a solution of 1-phenyl-1,4-pentanedione (1.06g, 6.0 mmol) and toluene (50 mL) was added p-phenetidine (0.78 mL, 6.0 mmol) and 5 drops of glacial acetic acid. The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (15-25% EtOAc/hexanes) to give 1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.17-7.13 (m, 2H), 7.10-7.05 (m, 5H), 6.89-6.84 (m, 2H), 6.35 (d, 1H), 6.08 (d, 1H), 4.04 (q, 2H), 2.13 (s, 3H), 1.44 (t, 3H); MS (ESI) 278 (M+H)⁺.

Acetyl chloride (0.36 mL, 5.0 mmol) and SnCl₄ (5.0 mL of a 1.0 M solution in CH₂Cl₂, 5.0 mmol) were added dropwise to a stirring solution of 1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole (554 mg, 2.0 mmol) and toluene (10 mL) at 0° C. The mixture was warmed to rt and then heated at 50° C. overnight. Following cooling to rt, the mixture was diluted with 1N NaOH (50 mL), extracted with EtOAc (100 mL), the organic layer washed with brine, dried (MgSO₄), filtered, concentrated in vacuo, and purified by flash chromatography on silica gel (0-30% EtOAc/hexanes). The resulting diacetylpyrrole was dissolved in EtOH (10 mL) and hydrazine (0.5 mL) and the mixture was heated at 50° C. for 2b. The mixture was cooled to rt and poured into ice water (50 mL). The resulting solid was filtered to give 6-(4-ethoxyphenyl)-5-phenyl-1,4,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.26-7.23 (m, 3H), 7.16-7.13 (m, 2H), 7.00-6.97 (m, 2H), 6.84-6.81 (m, 2H), 3.99 (q, 2H), 2.87 (s, 3H), 2.53 (s, 3H), 2.27 (s, 3H), 1.40 (t, 3H); MS (M+H)⁺ 358.58.

Other variations or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention. This invention is not to be limited except as set forth in the following claims. 

1. A method of binding the α₂δ subunit of voltage gated calcium channels comprising a step of administering an effective amount of a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents; R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents; and R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; and provided that the compound is not selected from the following table:


2. The method according to claim 1, wherein R¹ is —C₀₋₆alkyl-aryl.
 3. The method according to claim 2, wherein R¹ is —C₀₋₆alkyl-phenyl.
 4. The method according to claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 5. A method of treatment of neuropathic pain comprising a step of administering an effective amount of a pharmaceutical composition comprising: a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
 6. The method according to claim 5, wherein said composition further comprising i) an opiate agonist, ii) an opiate antagonist, iii) an mGluR5 antagonist, iv) a 5HT receptor agonist, v) a 5HT receptor antagonist, vi) a sodium channel antagonist, vii) an NMDA receptor agonist, viii) an NMDA receptor antagonist, ix) a COX-2 selective inhibitor, x) an NK1 antagonist, xi) a non-steroidal anti-inflammatory drug, xii) a GABA-A receptor modulator, xiii) a dopamine agonist, xiv) a dopamine antagonist, xv) a selective serotonin reuptake inhibitor, xvi) a tricyclic antidepressant drug, xvii) a norepinephrine modulator, xviii) L-DOPA, xix) buspirone, xx) a lithium salt, xxi) valproate, xxii) neurontin, xxiii) olanzapine, xxiv) a nicotinic agonist, xxv) a nicotinic antagonist, xxvi) a muscarinic agonist, xxvii) a muscarinic antagonist, xxviii) a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), xxix) a heroin substituting drug, xxx) disulfiram, or xxxi) acamprosate.
 7. The method according to claim 6, wherein said heroin substituting drug is methadone, levo-alpha-acetylmethadol, buprenorphine or naltrexone.
 8. A method of treatment or prevention of pain comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 9. A method of treatment or prevention of a pain disorder wherein said pain disorder is acute pain, persistent pain, chronic pain, inflammatory pain, or neuropathic pain, comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 10. A method of treatment or prevention of anxiety, depression, bipolar disorder, psychosis, drug withdrawal, tobacco withdrawal, memory loss, cognitive impairment, dementia, Alzheimer's disease, schizophrenia or panic comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 11. A method of treatment or prevention of disorders of extrapyramidal motor function comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 12. The method of claim 11 wherein said disorder of extrapyramidal motor function is Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome, or tardive dyskinesia.
 13. A method of treatment or prevention of anxiety disorders comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 14. The method of claim 13 wherein said anxiety disorder is panic attack, agoraphobia or specific phobias, obsessive-compulsive disorders, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, eating disorder, substance-induced anxiety disorder, or nonspecified anxiety disorder.
 15. A method of treatment or prevention of neuropathic pain comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 16. A method of treatment or prevention of Parkinson's Disease comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 17. A method of treatment or prevention of depression comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 18. A method of treatment or prevention of epilepsy comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 19. A method of treatment or prevention of inflammatory pain comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 20. A method of treatment or prevention of cognitive dysfunction comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 21. A method of treatment or prevention of drug addiction, drug abuse and drug withdrawal comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 22. A method of treatment or prevention of bipolar disorders comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 23. A method of treatment or prevention of circadian rhythm and sleep disorders comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 24. The method of claim 23 wherein the circadian rhythm and sleep disorders are shift-work induced sleep disorder or jet-lag.
 25. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 26. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents; R², R⁴, R³, and R⁵ each independently is —C₀₋₆alkyl, —C₀₋₆alkyl-aryl, —C₀₋₆alkyl-heteroaryl, —C₀₋₆alkyl-C₃₋₆cycloalkyl, or —C₀₋₆alkyl-heteroC₃₋₇cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —OR⁶, —NR⁶R⁷, —C(═NR⁶)NR⁷R⁸, —N(—NR⁸⁸R⁶)NR⁷R⁸, —NR⁶COR⁷, —NR⁶CO₂R⁷, —NR⁶SO₂R⁸⁸, —NR⁶CONR⁷R⁸, —SR⁸⁸, —SOR⁸⁸, —SO₂R⁸⁸, —SO₂NR⁶R⁷, —COR⁶, —CO₂R⁶, —CONR⁶R⁷, —C(═NR⁶)R⁷, or —C(═NOR⁶)R⁷ substituents; and R⁶, R⁷, R⁸, and R⁸⁸ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) substituents; provided that the compound is not 6-methyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine, 5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine, N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzamide, 1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate, 1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine, 5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 5,7-dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide, 2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafloroborate 5,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine, 5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine, 6-benzyl-1,4-diphenyl-5-p-tolyl-6H-pyrrolo[3,4-d]pyridazine, 6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine, 6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline, 11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline, 6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine, 9,12-diphenyl-pyridazino[4′, 5′:3,4]pyrrolo[2, 1-a]isoquinoline, 5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester, 7,10-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline, 11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine, 1-oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2,1-c]benzoxazine-1,4,10-methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine, 1-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine, 1,4-dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1-chloro-4-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride, 1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 5-cyano-1,4-dimethylpyridazino[4,5-a]indolizine, 1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile, 5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine, 6-methyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 5,7-dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile, dimethyl 3,12,13,17-tetramethyl-7²,7³-diazabenzo[g]porphyrin-2,18-dipropionate, 5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol, 5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride, 3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4d]pyridine, or 1,4-diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole; and is not selected from the following table: 